systemic antibiotics versus topical treatments for ...complications, healingtheeardrum, andimproving...

Systemic antibiotics versus topical treatments for chronically

discharging ears with underlying eardrum perforations

(Review)

Macfadyen CA, Acuin JM, Gamble C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2006, Issue 4

http://www.thecochranelibrary.com

1Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)

Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

http://www.thecochranelibrary.com

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

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .

4SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .

5METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .

16ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38Table 01. Methodological quality of included studies . . . . . . . . . . . . . . . . . . . . . .

42Table 02. Bilateral Disease: Numbers for Ears vs Participants . . . . . . . . . . . . . . . . . . . .

45Table 03. Participant eligibility criteria, including CSOM diagnostic criteria . . . . . . . . . . . . . .

54Table 04. Intervention regimens used . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61Table 05. Outcomes assessed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70Table 06. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73Table 07. Supiyaphun 2000 hearing analysis: pre- and post-treatment audiometry (2 weeks) . . . . . . . . .

73Table 08. Supiyaphun 2000 hearing analysis: Ototoxic rate . . . . . . . . . . . . . . . . . . . .

73ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73Comparison 01. Systemic antibiotic vs topical antiseptic . . . . . . . . . . . . . . . . . . . . .

73Comparison 02. Systemic antibiotic versus topical antibiotic . . . . . . . . . . . . . . . . . . . .

73Comparison 03. Systemic antibiotic vs systemic + topical antibiotic . . . . . . . . . . . . . . . . .

74Comparison 04. Systemic + topical antibiotic vs topical antibiotic . . . . . . . . . . . . . . . . . .

74INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

74COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75Analysis 01.01. Comparison 01 Systemic antibiotic vs topical antiseptic, Outcome 01 Treatment failure (persistent

discharge) at 2-4 weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76Analysis 02.01. Comparison 02 Systemic antibiotic versus topical antibiotic, Outcome 01 Treatement failure (persistent

discharge) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77Analysis 03.01. Comparison 03 Systemic antibiotic vs systemic + topical antibiotic, Outcome 01 Systemic quinolone vs

systemic + topical quinolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77Analysis 04.01. Comparison 04 Systemic + topical antibiotic vs topical antibiotic, Outcome 01 Systemic+topical non-

quinolone vs topical quinolone . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78Analysis 04.02. Comparison 04 Systemic + topical antibiotic vs topical antibiotic, Outcome 02 Treatment failure

(persistent discharge) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iSystemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)


Systemic antibiotics versus topical treatments for chronicallydischarging ears with underlying eardrum perforations(Review)

Macfadyen CA, Acuin JM, Gamble C

This record should be cited as:

Macfadyen CA, Acuin JM, Gamble C. Systemic antibiotics versus topical treatments for chronically discharging ears with

underlying eardrum perforations. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005608. DOI:

10.1002/14651858.CD005608.

This version first published online: 25 January 2006 in Issue 1, 2006.

Date of most recent substantive amendment: 15 November 2005

A B S T R A C T

Background

Chronic suppurative otitis media (CSOM) causes ear discharge and impairs hearing.

Objectives

To compare systemic antibiotics and topical antiseptics or antibiotics (excluding steroids) for treating chronically discharging ears with

an underlying eardrum perforation (CSOM).

Search strategy

The Cochrane ENT Disorders Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane

Library Issue 1, 2005), MEDLINE (January 1951 to March 2005), EMBASE (January 1974 to March 2005), LILACS (January

1982 to March 2005), AMED (1985 to March 2005), CINAHL (January 1982 to March 2005), OLDMEDLINE (January 1958 to

December 1965) PREMEDLINE, Metadatabase of registers of ongoing trials (mRCT), and article references.

Selection criteria

Randomised controlled trials; any systemic versus topical treatment (excluding steroids); participants with CSOM.

Data collection and analysis

One author assessed eligibility and quality, extracted data, entered data into RevMan; two authors provided a second assessment of

titles and abstracts, and inputted where there was ambiguity. We contacted investigators for clarifications.

Main results

Nine trials (833 randomised participants; 842 analysed participants or ears). CSOM definitions and severity varied; some included

mastoid cavity infections, other diagnoses, or complications. Methodological quality varied; generally poorly reported, follow-up short,

handling of bilateral disease inconsistent. Topical quinolone antibiotics were better than systemic antibiotics at clearing discharge at 1-

2 weeks: relative risks (RR) were, 3.21 (95% confidence interval (CI) 1.88 to 5.49) using systemic non-quinolone antibiotics (2 trials,

N = 116), and 3.18 (1.87 to 5.43) using systemic quinolone (3 trials, N = 175); or 2.75 (1.38 to 5.46) in favour of systemic plus topical

quinolone over systemic quinolone alone (2 trials, N = 90). No statistically significant benefit was seen at 2-4 weeks for topical non-

quinolone antibiotic (without steroids) or topical antiseptic over systemic antibiotics (mostly non-quinolones), but numbers were small:

one trial tested topical non-quinolones (N = 31); two tested antiseptics (N = 152). No benefit of adding systemic to topical treatment

at 1-2 weeks was detected either, although evidence was limited (three trials, N = 204). Evidence regarding safety was generally weak.

Adverse events reported were generally mild, although hearing worsened by ototoxicity (damaging auditory hair cells) was seen with

chloramphenicol drops (non-quinolone antibiotic).



Authors’ conclusions

Topical quinolone antibiotics can clear aural discharge better than systemic antibiotics; topical non-quinolone antibiotic (without

steroids) or antiseptic results are less clear. Evidence regarding safety was weak. Further studies should clarify topical non-quinolones

and antiseptic effectiveness, assess longer-term outcomes (for resolution, healing, hearing, or complications), and include further safety

assessments, particularly to clarify the risks of ototoxicity and whether there may be fewer adverse events with topical quinolones than

other topical or systemic treatments.

P L A I N L A N G U A G E S U M M A R Y

A Cochrane systematic review comparing systemic antibiotics and topical treatments for chronically discharging ears with underlying

eardrum perforations, in participants of any age

Chronic suppurative otitis media (CSOM) is an infection of the middle ear with pus and a persistent perforation in the eardrum. It is a

common cause of preventable hearing impairment, particularly in low and middle-income countries. This review compares alternative

topical treatments (antibiotics or antiseptics) with systemic (e.g. oral or injected) antibiotics, to identify which is best. Nine randomised

controlled trials were included (833 randomised participants; 842 analysed participants or ears); most were poorly reported and some

included a range of diagnoses.

Quinolone antibiotic drops such as ciprofloxacin were better than oral or injected antibiotics at drying the ear. This was found when

compared to systemic quinolone or non-quinolone antibiotics. No benefit of adding systemic treatment to topical antibiotics was

detected, although evidence was limited. The effects of topical non-quinolone antibiotics (without steroids) or antiseptics were less clear

when compared to systemic treatment. Less is known about longer-term outcomes (producing a dry ear in the long-term, preventing

complications, healing the eardrum, and improving hearing), or about treating complicated CSOM. The evidence in these trials about

safety is also weak. More research is needed to assess whether there may be fewer adverse events with topical quinolones than with

alternative topical or systemic treatments.

B A C K G R O U N D

Chronically discharging ears associated with underlying persistent

eardrum perforations (chronic suppurative otitis media, CSOM)

are a common cause of preventable hearing impairment world-

wide, particularly in low and middle-income countries (McPher-

son 1997; WHO 1998). CSOM usually occurs in the first five

years of life (although it often persists into adulthood), and is re-

lated to poor socio-economic conditions. Therefore, while this re-

view aims to address the global perspective of CSOM, much of

the information discussed here relates to low-income settings and

may differ in developed countries (e.g. age distribution).

What is CSOM?

CSOM is one of several types of otitis media (infection of the

middle ear). The World Health Organization defines CSOM as

“a stage of ear disease in which there is chronic infection of the

middle ear cleft, a non-intact tympanic membrane (i.e. perforated

eardrum) and discharge (otorrhoea), for at least the preceding two

weeks” (WHO 1998), although this could more strictly be con-

sidered a childhood definition. Perforations and infection can be

in one ear (unilateral) or both (bilateral). A variety of underlying

pathologies can cause CSOM including: an acute episode of acute

otitis media that has burst the ear drum and not settled within

two weeks; a recurrent episode of acute otitis media in an ear with

a perforation from a previous episode of acute otitis media; or an

ear with a persistent perforation with active chronic otitis media

with metaplastic changes to the mucosa of the middle ear and mas-

toid air cell system (Browning 2003, personal correspondence). In

adults, the majority of patients are likely to have CSOM with a

perforation that will not spontaneously heal.

What are the effects of CSOM?

Hearing impairment, aside from the disability from recurrent ear

discharge, is the most frequent effect of CSOM. A school survey

in Kenya found 63% of ears with CSOM had more than 30 deci-

bels hearing loss, compared to only 3.4% of ears without outer or

middle ear pathology (Hatcher 1995). Hearing impairment due

to otorrhoea and a perforated eardrum will usually improve as the

disease resolves. However, untreated CSOM may result in perma-

nent hearing loss due to damage to the ossicles which transmit

sound vibrations from the eardrum to the cochlea. Because otitis

media occurs mostly in children during pre-school years, the years

in which the most dynamic phase of speech and language develop-

ment occurs, there is concern that the associated hearing deficits

may result in speech and language delays or permanent learning

disabilities, as well as disturbances in behaviour (Klein 2001).

In addition to hearing impairment (with its associated conse-

quences), complications of otitis media can often result in death or



severe disability, especially in low-income countries (WHO 2000),

where immunity, housing conditions, and access to medical ser-

vices are often poorer than in high income settings. The infec-

tion may extend and spread to the head and neck structures and

to the brain. Intracranial infections include meningitis, abscesses,

hydrocephalus, or thrombosis of the lateral venous sinus (from

suppuration within the mastoid causing clots occluding the lumen

of the vessel) (Ludman 1997). Alternatively complications may

be extracranial, such as subperiosteal abscess (superficial accumu-

lations of pus that have broken the bony mastoid cortex), facial

paralysis, cholesteatoma (a destructive formation of layers of ker-

atinising epithelium, accumulating in the middle ear and mastoid

(Bluestone 1996), also described as ’active squamous (epithelial)

chronic otitis media’ (Browning 1997)), labyrinthitis (extension

to the labyrinth through the round window), or acute mastoidi-

tis (spread of the infection to the mastoid air cells), which may

spread further due to necrosis of the bony wall of the cells resulting

in further life-threatening complications (Dhillon 1999; Ludman

1997).

How much of a burden is CSOM?

Around 91% of the burden of otitis media (all types) and nearly

all related deaths occur in low and middle-income countries

(WHO 2002; World Bank 1993). Reliable data on prevalence of

CSOM are uncommon. One study estimated it at 1.1% in Kenyan

schoolchildren (Hatcher 1995) and a review of school and com-

munity-based studies reported a prevalence between 0.4% and

6.1% in low and middle-income countries (Berman 1995). Data

from the World Health Organization and World Bank suggest

the global burden of otitis media (of all types) has dropped dra-

matically since 1990, to approximately 6000 deaths (0.01% of all

deaths) and 1,474,000 disability adjusted life years (DALYs) lost

(0.1% of all DALYs) worldwide in 2001 (WHO 2002). Most of

these deaths are likely to be due to chronic otitis media and its

complications, because acute otitis media is usually a self-limiting

infection (Acuin 2004).

Although most of the background literature cited in this review

relates to children, reliable and generalisable data for the global

burden in children are not readily available; the WHO estimates

therefore quoted here are for both adults and children.

What are the causes of CSOM?

The causes and risk factors associated with CSOM are unclear,

and few studies have examined these for CSOM. Instead authors

have extrapolated results of studies for acute otitis media and otitis

media with effusion to CSOM. However, these studies often have

conflicting findings, and there is no proven correlation between

the various host and environmental factors associated with CSOM

and the factors associated with acute otitis media and otitis me-

dia with effusion. Despite this, some important factors that may

be associated with CSOM include: environmental factors such as

inadequate treatment (of CSOM and acute otitis media), poor

access to medical care, poor socioeconomic conditions, season,

exposure to tobacco smoke, overcrowding, attendance at day care

centres, lack of breastfeeding, or poor nutrition or hygiene; and

host factors such as altered immunity and underlying diseases (e.g.

HIV/AIDS (Barnett 1992; Singh 2003), frequent upper respira-

tory tract infections), early onset of otitis media in the first months

of life, and family history of otitis media. Some populations are

at increased risk of developing CSOM, and have high rates re-

ported, including certain ethnic groups (such as Native American

tribes of Apache and Navajo, Australian Aborigines, and Inuits of

Canada, Greenland and Alaska), and individuals with anatomical

defects (e.g. cleft palate or submucous cleft), altered physiologi-

cal defences (Eustachian tube dysfunction) or Down’s syndrome

(Bluestone 1998).

What management approaches are there?

The aims of treatment are to stop the discharge (and to eradicate

infection), to heal the tympanic membrane, improve hearing, pre-

vent the common problems of recurrent or new infections, and to

prevent potentially life-threatening complications. Treatment op-

tions for uncomplicated CSOM include dry mopping, ear wick-

ing, gentle syringing, or suctioning, to clean the ear discharge (au-

ral toilet); systemic antibiotics (e.g. oral antibiotic preparations,

or intravenous antibiotics); and topical treatment with either an-

tiseptics or antibiotics, sometimes with steroids. If complications

develop, surgery is usually required to remove the infected tissue

from the middle ear and mastoid air cells, and possibly repair the

damaged eardrum and ossicles. Each of these treatments will be

considered in the following Cochrane reviews:

• aural toilet: aural toilet versus no treatment or various methods

of aural toilet

• systemic antibiotic treatment: systemic antibiotics versus no treat-

ment or aural toilet, or various methods of systemic antibiotics

• topical antiseptics: topical antiseptic versus no treatment or aural

toilet, or various topical antiseptics

• topical antibiotics without steroids: topical antibiotic, versus no

treatment or aural toilet, topical antiseptics or various topical

antibiotics, excluding steroids (Macfadyen 2005b)

• systemic versus topical treatments for CSOM (THIS REVIEW):

any systemic treatment against any topical treatment excluding

steroids

• systemic or topical steroids: steroids, as monotherapy or combi-

nation therapy, versus no treatment or aural toilet, topical an-

tiseptics, topical antibiotics, or systemic antibiotics

• surgical treatment: surgery versus no treatment or any other treat-

ment

A report of a WHO/CIBA Foundation Workshop held in 1996,

recommends administration of topical (and/or systemic) antibi-

otics as well as dry mopping/wicking, since wicking alone is felt to

be ineffective (as found by Smith 1996) (WHO 1998). However,



the WHO guidelines still currently recommend treating CSOM

by using wicking to dry the ear alone (and a five-day follow up).

Systemic versus topical treatment

A number of topical antibiotics and antiseptics have been used

in the treatment of CSOM. However, concern exists regarding

their ability to penetrate the middle ear and mastoid cavities as

well as their activity against the causative bacteria (usually gram-

negative). There also remains controversy and uncertainty about

the possible ototoxic effect, in particular of topical aminoglycoside

antibiotics (by damaging the hair cells in the basal turn of the

cochlea), particularly where the eardrum is not intact. For this

reason, systemic treatments are still often recommended and used

in preference over topical antibiotics, where the eardrum is not

intact. However, topical treatment may be superior to systemic

treatment in terms of efficacy and also safety, although this needs

investigating, particularly as systemic antibiotics are often more

easily available and remain widely used in many low and middle-

income settings.

O B J E C T I V E S

To compare the effects of systemic and topical treatments (exclud-

ing steroids) for chronically discharging ears with an underlying

eardrum perforation (CSOM) in participants of any age.

C R I T E R I A F O R C O N S I D E R I N G

S T U D I E S F O R T H I S R E V I E W

Types of studies

Individual randomised controlled trials.

Cluster randomised controlled trials.

Types of participants

People of any age with a diagnosis of CSOM as defined by the

trial authors.

Types of intervention

Intervention: any systemic treatment excluding steroids.

Comparator: any topical (aural) treatment excluding steroids.

(Treatments containing steroids will not be included here, but will

be considered in a separate Cochrane review, as indicated above).

Comparisons may also include systemic or topical treatment versus

a combination of systemic and topical treatment.

Types of outcome measures

Primary

• Resolution of CSOM at 2 to 4 weeks, and after 4 weeks, ac-

cording to the investigators’ criteria

Secondary

• Healing of perforation at 2 to 4 weeks, and after 4 weeks

• Time to resolution of CSOM as defined by the investigators

• Improvement in hearing threshold, as measured by audiometry

at 2 to 4 weeks, and after 4 weeks

• Time to re-appearance of discharge and perforation after its

previous resolution

• Adverse events that

a) are fatal, life-threatening, require inpatient hospitalisation or

prolongation of existing hospitalisation, or result in persistent or

significant disability/incapacity, such as permanent hearing loss,

tinnitus or vertigo (Karbwang 1999; UMC 2003)

b) result in withdrawal or discontinuation of treatment

c) any other adverse events, such as ear pain, ear canal reactions

and transient dizziness

Where outcomes (resolution of discharge, healing of the tympanic

membrane, and hearing threshold) are reported at several time-

points within the ranges above, we took the last reported result.

S E A R C H M E T H O D S F O R

I D E N T I F I C A T I O N O F S T U D I E S

See: Cochrane Ear, Nose and Throat Disorders Group methods

used in reviews.

The Trials Search Co-ordinator of the Cochrane ENT Group

carried out an independent search in August 2003 and March

2005.

We attempted to identify all relevant studies regardless of

language or publication status (published, unpublished, in press,

and in progress). Trials reported in conference proceedings or on

posters have not been sought for this review, but will be sought

for inclusion in an update of this review.

We searched the Cochrane ENT Disorders Group Specialised

Register (code SR-ENT), and the Cochrane Central Register

of Controlled Trials (CENTRAL), published in The Cochrane

Library Issue 1, 2005, for relevant trials up to March 2005. Full

details of the Cochrane ENT Disorders Group methods and the

journals handsearched are published in The Cochrane Library in

the section on Collaborative Review Groups.

CENTRAL was searched using the following terms:

#1 OTITIS MEDIA SUPPURATIVE single term (MeSH)

#2 OTITIS MEDIA explode all trees (MeSH)

#3 otitis media

#4 #2 OR #3

#5 SUPPURATION explode all trees (MeSH)

#6 suppurat* OR purulen* OR PUS

#7 #5 OR #6



#8 #4 AND #7

#9 CHRONIC DISEASE explode all trees (MeSH)

#10 CHRONIC* OR PERSIST*

#11 #9 OR #10

#12 #1 AND #11

#13 #8 AND #11

#14 #12 OR #13

#15 CHRONIC* NEAR DISCHARG*

#16 PERSIST* NEAR DISCHARG*

#17 #15 OR #16

#18 #4 AND #17

#19 CSOM OR OTORRH* OR OTORH*

#20 #14 OR #18 OR #19

#21 MASTOIDITIS single term (MeSH)

#22 MASTOIDITIS

#23 TYMPANIC MEMBRANE PERFORATION single term

(MeSH)

#24 EAR* NEAR DRUM* OR EARDRUM* OR TYMPANIC

#25 PERFORAT* OR RUPTUR*

#26 #24 AND #25

#27 #20 OR #21 OR #22 OR #23 OR #26

#28 ANTI-INFECTIVE AGENTS explode all trees (MeSH)

#29 ACETIC ACID explode all trees (MeSH)

#30 BORIC ACIDS explode all trees (MeSH).

#31 antibiot* OR antibact* OR antisept* OR antiinfect*

OR microbides OR bacteriocid* OR antimicrobial* OR

antimycobact*

#32 anti NEXT biot* OR anti NEXT bact* OR anti NEXT

sept* OR anti NEXT infect* OR anti NEXT mycobact* OR anti

NEXT microbial*

#33 borax OR boric OR hydrogen peroxide OR iodine OR

acetic acid OR burow* OR acetate* OR acetyl

#34 #28 OR #29 OR #30 OR #31 OR #32 OR #33

#35 #27 AND #34

#36 OTITIS-MEDIA-SUPPURATIVE-QT.DE.

#37 #35 OR #36

We also searched the following electronic databases using the

search terms provided above, in combination with the search

strategy for identifying trials developed by The Cochrane

Collaboration (Clarke 2003).

(1) MEDLINE (January 1951 to March 2005)

(2) EMBASE (January 1974 to March 2005)

(3) LILACS (www.bireme.br; January 1982 to March 2005)

(4) AMED (1985 to March 2005)

(5) CINAHL (January 1982 to March 2005)

(6) OLDMEDLINE (January 1958 to December 1965)

(7) PREMEDLINE

(8) NNR

(9) ZETOC

We searched the following potential sources of trials:

• mRCT (Metadatabase of registers of ongoing trials accessible

via the Internet: http://controlled-trials.com/mrct/)

• ENT Disorders Group Trials Register for any relevant abstracts

from conference proceedings

• Reference lists of all articles/trials identified by the above

methods (includes searching of bibliographies for relevant

citations)

• Previous published Cochrane Review, ’Interventions for

chronic suppurative otitis media’ (Acuin 1998)

• Other previously published (systematic) reviews: ’Chronic

suppurative otitis media’, in Clinical Evidence (Acuin 2004),

and ’Systematic Review of Existing Evidence and Primary Care

Guidelines on the Management of Otitis Media (Middle Ear

Infection) in Aboriginal and Torres Strait Islander Populations,

March 2001 (Couzos 2001)

• DARE using issues 2 and 3 of the Cochrane Library 2003 -

searched for systematic reviews

We will explore the following potential sources of trials for future

updates of this review:

• Other previously published (systematic) reviews identified by

the above search strategy.

• Organisations and individual researchers working in the field

of otitis media (including authors of published trials and other

experts who may know about additional trials).

• Pharmaceutical companies (see published notes for list of

companies contacted) to locate additional studies, unpublished

data, confidential reports, and raw data of published trials.

M E T H O D S O F T H E R E V I E W

Eligibility assessment

Carolyn Macfadyen (CM) and Jose Acuin (JA) independently

reviewed the titles and abstracts identified by the search strategy

to identify potentially relevant trials.

CM retrieved the full papers for all potentially relevant studies,

and assessed their eligibility to be included in the review using an

eligibility form based on the stated inclusion criteria. We identified

multiple publications from the same data set and reported these

as one trial. Where outcomes are not reported, we contacted the

author of the paper for this information, as the data may have

been collected but not reported. We excluded studies that do not

meet the inclusion criteria for this review and stated the reason

in the ’Characteristics of excluded studies’. Where necessary, we

contacted the study authors for clarification.

JA and Carrol Gamble (CG) provided a second opinion on trials

CM had selected for inclusion, and the three authors resolved any

disagreements through discussion.



Assessment of methodological quality

CM assessed the methodological quality of all the trials identified

as eligible for inclusion. CG reviewed trials where there was any

ambiguity about the methods used, and JA provided further

information where this had already been obtained from authors

of trials included in the previous review ’Interventions for chronic

suppurative otitis media’ (Acuin 1998). Any disagreements were

resolved through discussion. Where necessary, we contacted the

study authors for further clarification.

We assessed the methodological quality of the trials in terms

of generation of allocation sequence, allocation concealment,

blinding and inclusion of randomised participants. We classified

generation of allocation sequence, allocation concealment, and

inclusion of randomised participants as adequate, inadequate and

unclear as outlined by Juni 2001. Blinding is classified as double

blind, single blind, or open.

Data collection

CM extracted data of study characteristics, including methods,

participants, interventions, and outcomes, and recorded these on

standard forms. JA provided further information where this had

been obtained from authors of trials included in the previous

review ’Interventions for chronic suppurative otitis media’ (Acuin

1998). In studies where data were insufficient or missing, we

contacted the authors of the original studies for additional data

and/or verification of methods, to clarify any uncertainties about

the data and the way in which they were collected, and to try to

obtain missing data.

CSOM can occur in one or both ears for each participant, which

means participants can be counted more than once if ears are used

as the unit of analysis. Where outcomes were reported in number

of ears only, we also attempted to obtain the values for number

of participants; numbers of ears were used where this information

could not be obtained. We checked the data and resolved any

discrepancies by referring to the trial report, through discussion.

Where possible we extracted data to allow an intention to treat

analysis (i.e. the analysis should include all the participants in the

groups to which they were originally randomly assigned). If the

number randomised and the numbers analysed were inconsistent,

we calculated a percent loss-to-follow-up and reported this

information in additional Table 01. For binary outcomes, we

recorded total number of participants (or ears, where participant

numbers were unavailable) and number with the event in each

group of the trial. For continuous outcomes, for each group, we

extracted the number of participants, and the arithmetic means

and standard deviations. If the data were reporting using geometric

means, we planned to extract standard deviations on the log scale.

We planned to extract medians and ranges, and report these in

additional tables if any trials reported these.

Data analysis

CM entered data into Review Manager 4.2.

In studies that enrolled people with otitis externa, draining surgical

cavities or acute otitis media, as well as CSOM, we only included

the results for just CSOM participants if the authors reported

accounting for diagnosis at randomisation (e.g. stratified by

diagnosis) and presented results by diagnosis. Where information

was not reported regarding whether alternative diagnostic groups

were accounted for at randomisation, we included all participants

(groups may be unbalanced, and decisions by trialists to report

subgroups may have been linked to trend). We also included

all participants where separate results were not available. See

additional Table 03 for details. For crossover trials, we have only

taken the results before participants were crossed over to the

alternative treatment, where possible; otherwise results for all

participants combining pre- and post-crossover data were used.

For binary data, we combined trials using relative risks (RR)

and 95% confidence intervals (CI). We combined trials with

continuous data using the weighted mean difference and its 95%

confidence interval. Where data have been reported using medians

and ranges, or there is evidence of skewed data, we reported

medians and ranges where possible (dividing mean by the standard

deviation; results of < 1.64 indicate a positive skew). If continuous

data were reported using geometric means, we combined the

findings on a log scale and report on the original scale.

Quinolone (e.g. ciprofloxacin) and non-quinolone antibiotics

(e.g. gentamicin) are presented as separate subgroups within each

comparison, but not combined across trials. This was done as there

is a clinical interest in the difference in effectiveness of quinolones

compared to non-quinolones, as quinolones are thought to be

more effective and safer but more expensive.

Where heterogeneity is considered to be present, and it remained

clinically appropriate to combine data, we also used DerSimonian

& Laird random effects model, and reported both fixed and

random effects results.

The primary analysis is of all eligible studies. If a sufficient number

of trials is available for future updates (not available for each

comparison in this version of the review), we will explore whether

heterogeneity can be explained using subgroup analyses or meta-

regression for the following factors: age (under 16, and adults 16

years or older), associated mopping (dividing studies into those

with some form of ear toilet, and those without), co-interventions

(dividing studies into those with treatment comparison alone,

and those with treatment comparison in combination with other

co-interventions), and methodological quality (initially excluding

studies of the poorest quality). Sensitivity analyses will also

be used to explore methodological quality (notably adequate

concealment), and trial design (e.g. cluster randomisation). We

will display the results for each sensitivity analysis according to the

subgroups within each methods category.

The sensitivity analysis will include the following, as outlined in

the statistical guidelines in the Cochrane ENT Group Guidelines



for Reviewers (CochraneENTGuideline updated November

2000).

(1) Repeat the analysis excluding unpublished studies (if any).

(2) Repeat the analysis excluding studies of the lowest quality

(already done if there is heterogeneity).

(3) If there are one or more very large studies, we will repeat the

analysis excluding these, to investigate how much they dominate

the results.

(4) Repeat the analysis excluding studies where people with CSOM

are only a subgroup of the participants included in the study,

for example, those that enrol people with otitis externa, draining

surgical cavities or acute otitis media, as well as CSOM.

Within this version of the review, trials where people with CSOM

are only a subgroup of the participants included in the study are

identified - see additional Table 03.

For this version of the review, we visually examined forest plots,

in conjunction with the chi2 test, using a 5% level of statistical

significance, and the I2 statistic. The I2 statistic describes the

percentage of the variability in effect estimates that is due to

heterogeneity rather than sampling error (chance). A value greater

than 50% may be considered substantial heterogeneity (Deeks

2004). There were insufficient trials to investigate publication bias

using funnel plots; this may be done in further updates of the

review.

D E S C R I P T I O N O F S T U D I E S

Search results

The electronic searches identified 649 citations in August and

September 2003, plus 698 citations in March 2005, including

four unpublished trials. Three additional trials were already known

to the authors: van Hasselt 1997; van Hasselt 1998; van Hasselt

2002. Macfadyen 2005a was also undertaken by two of the au-

thors. Trials with duplicate publications were identified and re-

ferred to under the main trial publication. Full texts of 127 trials

were reviewed, and nine included as eligible for this review - see

breakdown of numbers below. We attempted to include all rele-

vant studies regardless of language.

• 127 trials: Full texts obtained for eligibility assessment (117

from the above sources, plus ten from reference lists and other

searches). Of these, 85 were in English only, three had English

and non-English publications, and 39 were in non-English lan-

guages only.

• 112 trials excluded: 79 English only, two English and non-

English language, 31 only available in non-English language.

• Six trials only available in non-English language, awaiting trans-

lation to determine eligibility.

• Nine trials included: six English only, one English and non-

English language, two only available in non-English language.

The Characteristics of Excluded Studies Table outlines reasons for

excluding studies following review of their full texts. The Charac-

teristics of Included Studies Table provides information on the in-

cluded trials; also see additional tables: Table 01 (methodological

quality of included studies); Table 02 (bilateral disease - numbers

for ears and participants); Table 03 (participant eligibility criteria,

including CSOM diagnostic criteria); Table 04 (intervention reg-

imens used); Table 05 (outcomes assessed).

Age, setting and location (for included studies)

See the Characteristics of Included Studies table for details.

Ages varied

• All studies included adults; four also included participants less

than 16 years old (with minimum ages between 6 and 15 years).

Details are reported in the characteristics of included studies

table and additional Table 03.

Setting

• No studies were reported to be community-based trials.

• Four were hospital based (ENT/outpatient departments); five

did not specify but also appear to hospital/clinic based.

Location

• Eight trials were in high-income countries (UK, Italy, Spain,

Gran Canaria, Greece and Hong Kong).

• One trial was in a low- or middle-income country (Thailand).

Diagnostic criteria for included participants

Additional Table 03 provides eligibility criteria and more detailed

CSOM diagnostic criteria. Definitions used for CSOM varied,

particularly for duration, and also whether positive bacterial cul-

ture or changes in mucosal appearance were assessed and/or re-

quired - see additional Table 03. We accepted the authors’ defini-

tions when assessing eligibility.

Four trials included cases with otorrhoea following mastoidectomy

(Browning 1983; Mira 1992; Papastavros 1989), tympanoplasty

(Mira 1992), or other surgery (de Miguel 1999). Two included os-

teitic or cholesteatomatous disease (de Miguel 1999; Papastavros

1989). Papastavros 1989 also included participants with a posi-

tive fistula sign and additional symptoms of complications. Papas-

tavros 1989 gave separate results for simple tubotympanic mucosi-

tis and atticoantral disease but not for any other findings. How-

ever, randomisation does not appear to be stratified by diagnosis

and all participants are included in this review. No other results

were reported separately for any trial, and all participants are in-

cluded in this review for these remaining trials. Additional Table

03 provides further details with numbers involved.

Interventions

Additional Table 04 provides details of the treatment regimens

used in the trials. The following treatments were assessed:

Topical antiseptics - two trials



• Boric acid and iodine powder (Browning 1983), and borax pow-

der or hydrogen peroxide drops (randomly allocated; Papas-

tavros 1989).

Systemic antibiotics alone - eight trials

• Two allocated one of a range of antibiotics within the treatment

arm, according to bacteriology:

*Browning 1983 used oral non-quinolones: penicillins (flu-

cloxacillin, cloxacillin, amoxicillin) and cephalosporins (oral

cephalexin); participants with Pseudomonas species were not ran-

domised to this group, due to resistance.

*Papastavros 1989 used a range of: oral and intravenous non-

quinolones [penicillins (oral amoxicillin plus clavulanate; intra-

venous piperacillin), macrolides (oral erythromycin), beta-lac-

tam (intravenous aztreonam, Azactam), and other non-quinolones

(oral metronidazole, or sulfamethoxazole plus trimethoprim)];

oral quinolones (ciprofloxacin); and quinolone plus non-

quinolone (oral ciprofloxacin plus metronidazole).

• The other six trials tested four different systemic antibiotics

alone:

* Three tested non-quinolones: oral penicillin (amoxicillin plus

clavulanate, Augmentin); intramuscular aminoglycoside (gentam-

icin sulfate); intramuscular cephalosporin (ceftizoxime).

* Three tested quinolones: oral ciprofloxacin.

Topical antibiotics alone - seven trials

• Six tested topical quinolones: four ciprofloxacin, two ofloxacin.

• One tested topical non-quinolones: aminoglycoside (gentam-

icin) or chloramphenicol, according to bacteriology (Browning

1983).

Systemic plus topical antibiotics combined - four trials

• Two tested non-quinolones: one intramuscular plus topical

cephalosporin (ceftizoxime); one oral penicillin (amoxicillin)

plus topical chloramphenicol.

• Two tested quinolones: oral plus topical ciprofloxacin.

Placebo - two trials

• One topical (normal saline) and one systemic.

Most trials disallowed other treatments for a period before and/or

during the study - see Table 04 for details and exceptions. Treat-

ment duration was usually between 5 and 14 days; two trials gave

treatment for longer. Three studies did not mention aural toi-

let (Esposito 1990; Esposito 1992; Povedano 1995); the rest ap-

peared to be comparable across groups, performing aural toilet for

all groups (usually suction/aspiration) either before the first dose

only or as necessary at each visit. However, further information

has been requested from authors of all trials to confirm the aural

toilet regimen. See Table 04 for more details of treatment regi-

mens. One trial included a crossover to the alternative treatment

for failures after two to three weeks (Papastavros 1989); pre- and

post-crossover numbers were not reported separately, and all cases

have been included in this review.

Outcomes

The Characteristics of Included Studies Table indicates which re-

view outcomes were covered by each trial. Additional Table 05 de-

scribes the definitions used by the trials, for each review outcome,

and how and when outcomes were measured and reported.

Treatment failure (persistent discharge) - eight trials

Eight trials reported CSOM resolution for inclusion in the pri-

mary outcome of this review. However, definitions varied, and

most only reported results before two weeks - see Table 05. Where

trials reported separate categories for ’cure’ and ’improvement’, we

have classed ’improvement’ as failure along with any other cases

of failure reported.

One further trial reported assessing an outcome in this category,

but did not provide sufficient results for this review (Mira 1992).

Healing of the perforation - no trials:

Yuen 1994 reported assessing the perforation size during the study

but did not provide results after treatment. Supiyaphun 2000 also

reported baseline perforation size but no subsequent results.

Time to resolution of CSOM - no trials

Improvement in hearing threshold - one trial:

See additional tables for Supiyaphun 2000: Table 07 for changes

in bone conduction and speech reception threshold, Table 08 for

ototoxic rate, and also Table 06 for a summary statement for oto-

toxicity. See also figure (comparison 04, outcome 01, subgroups

02 and 03).

Four other trials assessed hearing, but only reported a summary

statement regarding lack of change (Yuen 1994) or worsening

in hearing or ototoxicity. Additional Table 06 (safety) provides

information regarding worsened hearing, where available.

Time to reappearance of discharge and perforation after its previous

resolution - no trials

However two trials reported absence of relapses two to three weeks

after treatment (Esposito 1990 and Esposito 1992).

Adverse events - six trials

Results of ototoxicity assessments and other adverse events col-

lected are reported in additional Table 06 (safety). One further

trial reported monitoring safety but did not provide results (Pa-

pastavros 1989).

Other outcomes assessed but not specified in the protocol for this review

- nine trials

See additional Table 05 for details of these outcomes, which have

not been analysed in this review.

Sources of support

Pharmaceutical company support - one trial (Supiyaphun 2000).



Two trials further reported provision of treatment by pharmaceu-

tical companies (Esposito 1990; Esposito 1992).

University committee grant - one trial (Yuen 1994).

Not mentioned - seven trials.

M E T H O D O L O G I C A L Q U A L I T Y

Additional Table 01 provides details of the methodological quality

of included studies.

Sequence generation

Two were “adequate”: Mira 1992; Yuen 1994.

One was “inadequate”: Papastavros 1989 - six high risk compli-

cated cases were allocated to systemic antibiotics, and not ran-

domised (results not presented separately). The remaining partic-

ipants were described as randomised, but did not discuss how se-

quence was generated, or how different diagnoses were accounted

for during randomisation.

Six were “unclear”: described as randomised, but did not discuss

how the sequence was generated, or how different diagnoses were

accounted for during randomisation.

Allocation concealment

One was “adequate”: Yuen 1994 (drawing concealed envelopes).

Eight were “unclear”: allocation concealment was not discussed

(three trials were described as single blind).

Blinding

Three trials were single-blind; six did not report on blinding.

Balance of baseline characteristics across groups

This was not reported in one trial. The rest reported at least one

characteristic by treatment group - see additional Table 01 for

details.

For the four trials that included a range of diagnoses, Mira 1992

reported numbers for each across treatment groups and was mostly

balanced; Papastavros 1989 reported type of disease (balanced),

but did not report other complications by group except the six

non-randomised complicated cases on systemic treatment, giving

a higher morbidity in this group. Browning 1983 and de Miguel

1999 did not present baseline numbers or results for each diagnosis

separately by treatment group.

Follow up (inclusion of randomised participants)

For the primary outcome, resolution or treatment failure:

Six were “adequate” (> 90% included):

Povedano 1995 stated that all participants completed the study

with no dropouts. Four further trials did not report any loss to

follow-up or exclusions.

Yuen 1994 reported a 7% (4/60) dropout rate - see Table 01.

Two were “unclear”:

Two trials each reported only one dropout but did not provide

the actual numbers or totals analysed for the results, to confirm

whether adequate numbers were included in the analysis (Mira

1992 and Supiyaphun 2000).

One was “inadequate”:

One trial reported 32% dropout for defaulters or non-compliers

(Browning 1983 - see Table 01).

Main reasons specified for exclusion were:

Non-compliance (used <75% of the medication: Browning 1983);

lack of attendance (loss to follow-up: Mira 1992; Supiyaphun

2000; Yuen 1994); adverse event (Yuen 1994).

Bilateral disease

Most trials analysed and presented results by participant, although

some reported ears instead, and most did not explain how bilat-

eral disease was treated or analysed. Additional Table 02 provides

detailed information regarding bilateral disease, and reporting of

ears versus participants, for each trial. Where available the number

of participants with bilateral disease for each trial is also presented.

Clarification has been requested from the authors for further in-

formation on handling bilateral cases and where numbers analysed

and totals for the results are unclear.

Results for ears - two trials

For bilateral disease each ear was treated and analysed as a separate

case. Rates of bilateral disease in these trials were 32% (Papastavros

1989) and 12.7% (Supiyaphun 2000).

However, Supiyaphun 2000 reported results as percentages of ears

with no actual numbers or totals, and rates reported do not equate

to whole ears when using the total numbers of ears excluding

dropouts (rates sometimes match number of participants more

closely). See additional Table 02.

Results for participants - seven trials

However, Mira 1992 reported overall scores without actual num-

bers or totals.

Only one trial specified how bilateral cases were handled (Brown-

ing 1983). See additional Table 02.

Where available, we have reported results for number of partici-

pants rather than ears; otherwise results for number of ears have

been taken. The concern is that a trial analysed by ears rather than

number of participants will have an underestimated standard error

and therefore receive an inappropriate increased weight in a meta-

analysis. We will use the information in Table 02 to attempt to

address the issues of inflated weighting for trials reporting num-

bers of ears, in a later update of this review.

R E S U L T S

See also additional tables (Table 02 for details regarding bilateral

disease in each trial, Table 04 for details of the treatment regimens



used for each of the sets of comparisons discussed below, and Ta-

ble 05 for the definitions and timings of the outcomes assessed

by trialists for each outcome category). Data relating to adverse

events and ototoxicity have been summarised in additional Table

06 for trials that mentioned this outcome. We have only presented

outcomes below that the trial authors have reported - see Table 05

for other outcomes. Clarification is being sought from the authors

where uncertainties exist in the data and where outcomes are not

reported. These responses will be incorporated in subsequent up-

dates of the review.

There were insufficient trials in each comparison to consider ex-

ploring heterogeneity or the sensitivity analyses outlined above;

these will be considered in a subsequent update of the review

if there are sufficient trials. Meanwhile, trials where people with

CSOM are only a subgroup of the participants included in the

study are identified in this review - see additional Table 03.

Do topical antiseptics work better than systemic antibiotics?

Two trials compared topical antiseptics to systemic antibiotics:

Browning 1983 compared topical antiseptic given once weekly

with daily systemic antibiotics. Although not stated in the trial

report, the authors confirmed that aural toilet was given in all

groups (weekly aural toilet by the otologist, using microscopic vi-

sion, and suction aspiration when necessary). Results were pre-

sented for participants, and also included those with draining mas-

toid cavities. Papastavros 1989 used a variety of antiseptics and

antibiotics (non-quinolone and quinolone) and also performed

toilet and debridement of the ear with suction as necessary for

both groups, performed at regular visits. Results were reported for

ears, and include both pre- and post-crossover data.

In both trials, the choice of antibiotics depended on baseline bac-

teriology results.

Treatment failure (persistent discharge) (Figure: comparison 01, out-

come 01)

Browning 1983 presented results after four weeks treatment. Clar-

ification has been sought from the authors of Papastavros 1989

for whether the results presented are after ten days or two to three

weeks treatment. Results for all diagnoses did not demonstrate any

statistically significant difference between groups: the RR (95%

CI) is 0.81 (0.61 to 1.08) in favour of antibiotics.

Adverse events

Browning 1983 did not mention this outcome; Papastavros 1989

collected details of systemic adverse effects and appearance of com-

plications or bothersome allergic reactions but results were not re-

ported. A request has been made to the authors for any available

results.

Do topical antibiotics alone work better than systemic antibi-

otics alone?

Comparisons between topical and systemic non-quinolones

One trial compared topical non-quinolone antibiotics alone to

systemic non-quinolones alone: Browning 1983 compared topical

chloramphenicol or gentamicin to a variety of systemic penicillins

or cephalosporin, treatment in both groups depending on base-

line bacteriology results. Both groups received weekly aural toilet

and suction aspiration when necessary. Results were presented for

participants.

Treatment failure (Figure: comparison 02, outcome 01, subgroup 01)

Results after four weeks (end of treatment) showed a trend in

favour of systemic antibiotics, although this crossed the line of no-

effect: RR (95% CI) 0.74 (0.46 to 1.19).

Comparisons between topical quinolones and systemic non-

quinolones

Two trials compared topical quinolone antibiotics alone with sys-

temic non-quinolones alone (Esposito 1992 and Yuen 1994). Es-

posito 1992 did not mention aural toilet, while Yuen 1994 gave

suction cleaning before the first dose only (both groups). Both

trials reported results at the participant level.


The results reported for Esposito 1992 appear to be for 12 hours

after five to ten days treatment, while Yuen reported results at week

two. The pooled results showed a significant effect in favour of

topical quinolone: RR (95% CI) was 3.21 (1.88 to 5.49).

No longer-term data were reported, although Esposito 1992 re-

ported that all participants who were clinically and bacteriologi-

cally cured 12 hours after five to ten days treatment, confirmed

their clinical status 14 and 21 days later; no relapses were observed.

A request has been made to the authors to confirm the total num-

bers at each occasion, and whether any additional cures were ob-

served.

Healing of the perforation

Esposito 1992 did not mention this outcome, while Yuen 1994

reported measuring size of perforation at each visit but did not

provide any results; a request has been made to the authors for any

available results.

Improvement in hearing threshold

Esposito 1992 measured audiometry and vestibular tests before

and 24 hours after treatment but only provided a summary state-

ment that “no worsening of the audiometric function related to lo-

cal or parenteral therapy was observed”. Yuen 1994 measured pure

tone audiometry, reporting for bone conduction at four frequen-

cies from 0.5 to 4kHz, but only reported a summary statement

that “there were no significant differences between the pre- and

post-treatment pure-tone audiograms of bone conduction thresh-

olds...” See additional Table 06 for both trials. A request has been

made to the authors for the results to be made available.

Adverse Events

Data relating to adverse events have been summarised in additional

Table 06.

Comparisons between topical and systemic quinolones



Three trials compared topical and oral ciprofloxacin (Esposito

1990; Povedano 1995; de Miguel 1999). de Miguel 1999 in-

cluded two treatment groups assessing topical ciprofloxacin alone

(at 0.2% and 0.5% strengths), for comparison with the treatment

group receiving topical plus oral ciprofloxacin - results for both

strengths are presented in this review. Only de Miguel 1999 dis-

cussed aural toilet, cleaning the ears by aspiration before starting

treatment only. All trials reported results at the participant level.


No trials reported results after 2 weeks: the results reported for

Esposito 1990 appear to be for 24 hours after five to ten days

treatment; Povedano 1995 reported results after 10 days treatment;

and clarification has been sought from the authors of de Miguel

1999 for whether the results relate to day 8 or 15.

The pooled RR (95% CI) is 3.18 (1.87 to 5.43) in favour of top-

ical antibiotic over systemic treatment. This uses the combined

results for both topical ciprofloxacin groups in de Miguel 1999,

as no difference in effectiveness for either strength had been de-

tected. Taking results for just 0.2% ciprofloxacin (3/25 failed) or

0.5% ciprofloxacin (4/25 failed) in the topical treatment group,

gives RR (95% CI): 3.33 (1.04 to 10.69) and 2.50 (0.90 to 6.92)

respectively for de Miguel 1999; and pooled results of RR (95%

CI): 3.36 (1.86 to 6.07) (tests for heterogeneity: I2=0%, chi2 p=

0.92); and 3.08 (1.75 to 5.44) (I2=0%, chi2 p=0.83), for 0.2%

and 0.5% groups respectively.




their clinical status 14 days later. A request has been made to

the authors to confirm the total numbers at each occasion, and

whether any additional cures were observed.


Povedano 1995 did not report this outcome. de Miguel 1999 and

Esposito 1990 reported recording this outcome (only for partic-

ipants receiving topical treatment in Esposito 1990) but neither

provided results except in a summary statement reporting a lack of

ototoxicity or related problems - see additional Table 06. A request

has been made to the authors for results to be made available.

Adverse events


Table 06. Povedano 1995 did not report this outcome; a request

has been made to the authors for any available results.

Does adding a topical antibiotic to a systemic antibiotic im-

prove treatment?

Adding topical non-quinolone to systemic non-quinolone:

One trial compared systemic non-quinolone alone with systemic

plus topical non-quinolones: Mira 1992 used intramuscular and

topical ceftizoxime. In both groups, aspiration of local secretions

was performed by the specialist before the fist dose only. Outcomes

were assessed at the participant level.

Treatment failure

Mira 1992 assessed the overall clinical course of disease (accord-

ing to fever, symptoms of infection and negative culture) but did

not provide results. In a summary statement, the authors reported

that there was no difference between the two groups of partici-

pants for the overall judgement expressed by the investigating doc-

tors, although a slightly higher success rate was recorded in the

systemic plus topical treatment group. Symptom severity scores

were also assessed at days 0, 3, 7 and 21, for otorrhoea, otalgia,

oedema and congestion; however the trial report only provided

overall scores per group over time, with p-values, but no numbers

assessed, standard deviations for average scores, or totals with each

score. In a summary statement, the authors stated there was a sig-

nificant difference in greater promptness of action using topical

treatment (significant difference between treatments at day three,

not significant by day seven), while intramuscular treatment alone

seemed to increase the risk of repeat infection, with a resurgence of

symptoms (significant difference in favour of systemic plus topical

treatment again at day 21). Further details have been requested

from the authors.

Adverse events


Table 06.

Adding topical quinolone to systemic quinolone

Two trials compared systemic ciprofloxacin alone with systemic

plus topical ciprofloxacin (de Miguel 1999 and Esposito 1990).

Only de Miguel 1999 discussed aural toilet, cleaning the ears by

aspiration before starting treatment only. Both trials reported at

the participant level.

Treatment failure (Figure: comparison 03, outcome 01)

No trials reported results after 2 weeks: the results reported for


treatment, and clarification has been sought from the authors of

de Miguel 1999 for whether the results relate to day 8 or 15.

The pooled RR (95% CI) is 2.75 (1.38 to 5.46) in favour of sys-

temic plus topical antibiotic over systemic treatment alone. No

longer-term data were reported, although Esposito 1990 reported

that all participants who were clinically and bacteriologically cured

24 hours after five to ten days treatment, confirmed their clini-

cal status 14 days later. A request has been made to the authors

to confirm the total numbers at each occasion, and whether any

additional cures were observed.


de Miguel 1999 and Esposito 1990 reported recording this out-

come (only for participants receiving topical treatment in Esposito

1990) but neither provided results except in a summary statement

reporting a lack of ototoxicity or related problems - see additional

Table 06. A request has been made to the authors for results to be

made available.

Adverse events




Table 06.

Does adding systemic antibiotic to a topical antibiotic improve

treatment?

Comparisons between systemic plus topical non-quinolone and

topical quinolone alone

One trial compared systemic and topical non-quinolone treat-

ment (oral amoxicillin plus topical chloramphenicol) with topical

quinolone alone (ofloxacin): Supiyaphun 2000. Aural toilet was

performed on Day 0 only for both groups. Results were reported as

percentage of ears at two weeks only. However, the actual numbers

or totals were not reported, and the rates reported do not equate

to whole ears, when taking the total numbers of ears excluding

dropouts. Clarification has been requested from the authors for

the actual numbers and confirmation of the unit of analysis.

Treatment failure at two weeks (Figure: comparison 04, outcome 01,

subgroup 01)

Results were reported for cure at two weeks only. Taking the re-

sults to the nearest whole number for ears and assuming all ears

were included in the analysis, the results were: RR (95% CI) 2.74

(1.52 to 4.94) in favour of topical quinolone antibiotic alone over

systemic plus topical non-quinolone antibiotic. A request has been

made to the authors to confirm whether any data were collected

after two weeks, and if so, for the results to be made available.


Table 07 shows changes in audiometry for Supiyaphun 2000. In

a summary statement, the authors reported that a significant im-

provement in bone conduction (p<0.001) and speech reception

threshold (p=0.002) was achieved in ofloxacin treated ears. Mean-

while a considerable deterioration (elevation) was observed in bone

conduction in amoxicillin plus chloramphenicol treated ears (p=

0.007). The authors did not report the numbers included in these

analyses and a request has been sent to the authors for this to be

provided.

Adverse events

Ototoxicity (Figure: comparison 04, outcome 01, subgroup 02 and

03):

Additional Table 08 provides the ototoxic rate per group, while

additional Table 06 gives a summary statement of the ototoxic-

ity in the systemic plus topical non-quinolone treatment group.

The authors found the ototoxic rate (percentage of ears in which

the elevation of bone conduction or speech reception threshold

was greater than 5dB or had a high frequency hearing loss, with

or without tinnitus) was also significantly higher in the systemic

amoxicillin plus topical chloramphenicol group than in topical

ofloxacin treated ears, which they attributed to the chlorampheni-

col. The authors did not report the numbers included in these

analyses and a request has been sent to the authors for this to be

provided. Taking the results for ototoxic rates to the nearest whole

number for ears and assuming all ears were included in the analysis

and results presented, the findings are RR (95%CI): 9.78 (2.43

to 39.37) for bone conduction and 2.54 (0.99 to 6.53) for speech

reception threshold (see figure).

Other adverse events:

Further data relating to other adverse events have been summarised

in additional Table 06.

Comparisons between systemic plus topical quinolone and top-

ical quinolone alone

Two trials compared systemic plus topical ciprofloxacin with top-

ical ciprofloxacin alone (de Miguel 1999 and Esposito 1990). de

Miguel 1999 included two groups with topical ciprofloxacin alone

(at 0.2% and 0.5% strengths) - results for both are presented in

this review. Only de Miguel 1999 discussed aural toilet, cleaning

the ears by aspiration before starting treatment only. Both trials

reported at the participant level.


No trials reported results after two weeks: the results reported for


treatment, and clarification has been sought from the authors of

de Miguel 1999 for whether the results relate to day 8 or 15.

The pooled results showed little difference between the systemic

plus topical versus topical quinolone treatment alone: RR (95%

CI) 1.17 (0.48 to 2.86). This uses the combined results for both

topical ciprofloxacin groups in de Miguel 1999, as no difference in

effectiveness for either strength had been detected. Taking results

for just 0.2% ciprofloxacin (3/25 failed) or 0.5% ciprofloxacin

(4/25 failed) in the topical treatment alone group, gives RR (95%

CI): 1.00 (0.22 to 4.49) and 0.75 (0.19 to 3.01) respectively for

de Miguel 1999; and pooled results of RR (95% CI): 1.33 (0.50

to 3.52) (I2=0%, chi2 p=0.61), and 1.14 (0.45 to 2.89) (I2=0%,

chi2 p=0.41) for 0.2% and 0.5% groups respectively.




their clinical status 14 days later. A request has been made to

the authors to confirm the total numbers at each occasion, and

whether any additional cures were observed.


de Miguel 1999 and Esposito 1990 reported recording this out-

come (only for participants receiving topical treatment in Esposito

1990) but neither provided results except in a summary statement

reporting a lack of ototoxicity or related problems - see additional

Table 06. A request has been made to the authors for results to be

made available.

Adverse events


Table 06.



D I S C U S S I O N

We excluded trials or comparisons with steroids (with or without

antibiotics; see steroids review), and presented findings for top-

ical antiseptics, topical antibiotics, and systemic plus topical an-

tibiotics separately, to address focused and meaningful questions.

These tighter comparisons and addition of new trials are why

minimal heterogeneity was observed in the comparisons presented

here and why some of our conclusions differ to those of an earlier

review (Acuin 1998). Although trials that mentioned aural toilet

appeared to use comparable regimens across groups, information

is being requested from the trials authors to confirm this was in-

deed the case, and also to obtain details for the three trials that did

not discuss aural toilet at all.

Two trials compared systemic antibiotic (mostly non-quinolones)

with topical antiseptic, and did not detect any statistically signifi-

cant differences between treatment groups for clinical cure. How-

ever the choice of antibiotic depended on bacterial results for both

trials, and Browning 1983 compared daily antibiotics with weekly

antiseptic. Results were only presented for up to three and four

weeks and included participants with draining mastoid cavities

and other complications.

Topical quinolone antibiotics alone were statistically significantly

better than systemic antibiotics alone. This was true for non-

quinolone and quinolone systemic treatments, both of which had

very similar treatment effects (pooled RR (95% CI) were: 3.21

(1.88 to 5.49) in favour of topical quinolones over systemic non-

quinolones, and 3.18 (1.87 to 5.43) for systemic quinolones).

Only one trial compared systemic antibiotics with topical non-

quinolones (giving a range of non-quinolones in both groups, ac-

cording to bacteriology; Browning 1983). This trial, which also

gave treatment for longer and presented results later than the other

trials (four weeks), was the only trial that did not find an effect in

favour of topical antibiotic treatment.

The effect of adding topical treatment to systemic treatment was

presented in two trials, both using only quinolone antibiotics.

Both reported higher cure rates at one to two weeks when topical

antibiotic was added to systemic treatment. However, the longer-

term results were not presented. One further trial reported a ben-

eficial effect of adding topical antibiotic to systemic treatment,

using non-quinolone antibiotics, but did not provide full results

(Mira 1992); further details have been requested from the authors

for the results of this trial.

Three trials assessed the effect of adding systemic antibiotics to top-

ical treatment (i.e. compared topical antibiotic alone to systemic

and topical antibiotics), all reporting results at one to two weeks

only. When using quinolones in both treatment groups (two tri-

als), no benefit was found when adding systemic antibiotics to top-

ical treatment, with no statistically significant difference for cure.

However, a statistically significant difference in favour of topical

antibiotic was found when systemic and topical non-quinolone an-

tibiotics were compared to topical quinolones (Supiyaphun 2000).

No trials found a statistically significant effect in favour of keep-

ing systemic antibiotic in the treatment regimen. This is a useful

finding, given the added cost and likely reduced adherence when

using a combination of treatments instead of monotherapy.

Systemic adverse effects noted by the authors included gastric com-

plaints and one case of skin rash. Topical effects were mainly local,

including fungal growth (otomycosis), pain on drops (37% with

chloramphenicol compared to 5.1% with ofloxacin in one trial,

Supiyaphun 2000), and tinnitus (one case, on oral amoxicillin

and topical chloramphenicol, which resolved on discontinuing the

drops: Supiyaphun 2000). Supiyaphun 2000 also report a signifi-

cant elevation (i.e. deterioration) of bone conduction and speech

reception threshold, and significantly higher ototoxic rates for par-

ticipants receiving oral amoxicillin and topical chloramphenicol

(non-quinolone) than for those on topical ofloxacin (quinolone),

which was attributed to the chloramphenicol. No other trials in

this review reported any worsening of audiometry results or evi-

dence of ototoxicity. However, ototoxicity has been observed for

various non-quinolone antibiotics, and aminoglycoside antibiotics

are not recommended in patients with a tympanic membrane per-

foration by the Medicines and Healthcare Products Regulatory

Agency (MHRA) in the UK (CSM 1997). One review of ototox-

icity cases in humans reported that ototoxicity may be primarily

due to vestibular damage (causing imbalance and dizziness) rather

than cochlear (Marais 1998), so assessments of hearing thresholds

for bone conduction alone would be unlikely to detect many cases

(Marais 1998; Lancaster 1999).

The follow-up period in all trials included here was short. No

trials assessed longer-term effects of treatment, or reported time

to resolution or to reappearance of discharge and perforation, or

results for healing of the tympanic membrane. As conclusions can

change over time, it may be important to investigate the longer-

term effects in future trials.

Most of the trials in this review were poor quality, with short

follow-up. Many included a range of participants (e.g. including

otitis externa, or draining mastoid cavities, or cholesteatomatous

disease). This may explain some of the heterogeneity found, since

resolution rates may vary widely between diagnoses, and so make

the results less applicable to any one type of disease. Trials were also

inconsistent in approaches for handling and reporting bilateral

disease. Where available, we have reported results for number of

participants rather than ears; otherwise results for number of ears

have been taken. The concern is that a trial analysed by ears rather

than number of participants will have an underestimated standard

error and therefore receive an inappropriate increased weight in a

meta-analysis. We will use the information obtained to attempt to

address the issues of inflated weighting for trials reporting numbers

of ears, in a later update of this review.



A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Short courses of topical quinolone antibiotics are more effective

than systemic antibiotics alone for the short-term resolution of ot-

orrhoea from uncomplicated CSOM. The effects of topical non-

quinolone antibiotics (without steroids) or antiseptics are less clear,

when compared to systemic treatment; no benefit of adding sys-

temic treatment to topical antibiotics was detected either, although

evidence was limited. Less is known about longer-term outcomes

(for dry ear, or to prevent complications, heal the eardrum, and

improve hearing), or about treating complicated CSOM. Evi-

dence regarding safety is also weak, and more research is needed

to clarify the risk of ototoxicity with alternative treatments (about

which there is much concern, particularly for topical aminoglyco-

sides), and whether there may be fewer adverse events with topical

quinolones than alternative topical or systemic treatments. Treat-

ment should therefore be accompanied by regular medical follow-

up and clinical vigilance, also monitoring for adverse effects of

treatment (particularly for local effects or signs of ototoxicity), or

for complications of the disease. Clinical staff should also advise

patients and their caregivers on appropriate ear care, with aural

toilet and effective instillation of the drops, ensuring the drops

reach the site of infection to work effectively.

Implications for research

Further trials should clarify the effects of non-quinolone antibi-

otics and antiseptics. Adequately designed and powered studies

should focus on the effects on the longer-term natural history

of CSOM, such as healing of the tympanic membrane, hearing

improvement, prevention of complications, and also on further

safety assessments. Other more comprehensive systematic reviews

should also assess safety further, particularly to verify the risks of

ototoxicity for alternative treatments. Trialists should also consider

how they handle bilateral disease and also the type of participants

included (or stratify randomisation by diagnosis if various diag-

noses are included), to ensure the results are clinically relevant to a

particular patient group. The cost effectiveness of alternative treat-

ments, preferably through economic evaluations alongside clini-

cal trials, would be valuable in guiding both clinical practice and

health policy.

N O T E S

This review, ’Systemic vs topical treatments for chronically dis-

charging ears with underlying eardrum perforations’ is one in a se-

ries of reviews, which replaces the review ’Interventions for chronic

suppurative otitis media’. Reviews of other interventions will fol-

low.

REVIEW HISTORY

Issue review first published: 1998/4 (Interventions for chronic

suppurative otitis media).

Date of most recent amendment: Information not available.

Date of most recent SUBSTANTIVE amendment: 12 February

1998.

Most recent changes:

February 1998.

October 2001: Cochrane review ’Interventions for chronic sup-

purative otitis media’ split into a series of Cochrane review titles,

each focusing on particular interventions.

Issue 1, 2004: Publish protocol for component review ’Topical an-

tibiotics for chronically discharging ears with underlying eardrum

perforations’.

DEVIATIONS FROM THE PROTOCOL

The following changes were made to the eligibility criteria and

outcome measures from those stipulated in the protocol:

1. ELIGIBILITY CRITERIA

Types of studies: quasi-randomised controlled trials were specified

in the protocol but excluded from the review.

Types of participants:

Protocol: People of any age with a diagnosis of CSOM meeting

the WHO definition

Review: any diagnosis of CSOM as defined by the trial authors.

Types of interventions - the following were stipulated in the pro-

tocol:

Intervention: topical (aural) antibiotics (all and individual)

Comparator: no intervention; placebo; other topical antibiotics

with and without steroids; systemic antibiotics (all and individual);

combination of topical and systemic antibiotics; antiseptics.

However, we have divided these trials into the following three

reviews:

* Topical treatment with antibiotics

comparisons: no treatment or aural toilet, topical antiseptics, var-

ious topical antibiotics, excluding steroids

* Systemic versus topical treatments for CSOM (THIS REVIEW)

comparisons: any systemic treatment against any topical treatment

excluding steroids

* Systemic or topical steroids, as monotherapy or combination

therapy

comparisons: no treatment or aural toilet, topical antiseptics, top-

ical antibiotics, systemic antibiotics

2. OUTCOMES

Types of outcome measures - the following primary outcomes have

been changed:

Protocol:

* Resolution of CSOM at 2 to 4 weeks and after 4 weeks, according

to the following findings:

a) No report of otorrhoea

b) Disappearance of discharge on otoscopy



c) Healing of the eardrum perforation on otoscopy

d) Time to resolution of CSOM according to any other defini-

tion of resolution made by the authors, including improvement

in mucosal appearance

Review:

* Resolution of CSOM at 2 to 4 weeks, and after 4 weeks, according

to the investigators’ criteria.

We have also analysed results for treatment failure rather than

success.

The others were analysed as separate, secondary outcomes (where

reported by trialists):

* Healing of perforation at 2 to 4 weeks, and after 4 weeks;

* Time to resolution of CSOM as defined by the investigators.

The other protocol outcomes were unchanged, except that results

before 2 weeks were also included and reported separately.

3. SEARCH STRATEGY

The protocol stated that we would obtain all relevant studies re-

gardless of publication status. However, trials reported in confer-

ence proceedings or on posters have not yet been sought, but will

be sought for inclusion in an update of this review. Additionally,

the further potential sources that we will search for future updates

of this review, were also specified in the protocol for this review.

4. METHODS - REVIEWERS’ CONTRIBUTIONS

The protocol stated that we would follow the statistical guidelines

in the Cochrane ENT Group Guidelines for Reviewers (Cochra-

neENTGuideline, updated November 2000), and that two re-

viewers (CM and JA) would independently:

* select trials (at least for electronic searches), review the titles and

abstracts of articles identified by the search strategy, and assess full

texts for eligibility;

* assess the methodological quality of all trials identified as eligible

for inclusion (and report the level of agreement between the two

reviewers);

* extract data of study characteristics, including methods, partici-

pants, interventions and outcomes, and record these on standard

forms; and

* enter data onto Review Manager 4.2.

However, while CM and JA independently reviewed titles and ab-

stracts of articles identified by the search strategy, only CM as-

sessed the full texts for eligibility and methodological quality, ex-

tracted data, and entered data onto Review Manager 4.2. JA and

CG provided a second opinion on trials CM had selected for in-

clusion; CG reviewed those where there was any ambiguity about

the methods used, for the methodological quality and data extrac-

tion; and JA provided further information where this had been

obtained from authors of trials included in the previous review

’Interventions for chronic suppurative otitis media’ (Acuin 1998).

The three authors resolved any disagreements through discussion.

5. ASSESSMENT OF METHODOLOGICAL QUALITY

The protocol stated that allocation concealment, and inclusion

of randomised participants, would be assessed as inadequate if an

allocation concealment approach was not reported, or it was not

clear how many people were originally randomised into the trial,

respectively. However, we have classed these as unclear.

We assessed the methodological quality of the trials using the fol-

lowing dimensions and criteria based on four methodological as-

pects.

a) Generation of allocation sequence

Adequate: if sequences are suitable to prevent selection bias and

the method used is described.

Adequate methods include random numbers generated by com-

puter, table of random numbers, drawing of lots or envelopes,

tossing a coin, shuffling cards, throwing dice, or other methods of

allocation that appear to be unbiased.

Unclear: stated but method not described.

The trial describes itself as being randomised but no further in-

formation is given.

Inadequate: if sequence could be related to prognosis.

Inadequate methods include case record number, date of birth,

time, day, month or year of admission.

b) Allocation concealment

Adequate: if participants and investigators enrolling participants

cannot foresee assignment. Adequate measures include a priori

numbered or coded containers of identical appearance, central

randomisation; sequentially numbered, opaque, sealed envelopes;

or other descriptions that contained convincing elements of con-

cealment.

Inadequate: trials in which the authors reported an approach that

could not be considered adequate (e.g. methods of allocation such

as alternation methods or use of case record numbers are not con-

cealed).

Unclear: trials in which the authors either did not report an allo-

cation concealment approach at all or allocation concealment was

stated but method not described.

Baseline comparison of experimental groups will confirm whether

treatment arm allocation appears to be unbiased.

c) Blinding

Double blind: the trial uses a placebo, or a double dummy tech-

nique such that neither the participant or care provider/assessor

know which treatment is given.

Single blind: the participant or care provider/assessor is aware of

the treatment given.

Open: all parties are aware of treatment.

d) Inclusion of all randomised participants



Adequate: More than 90% of people randomised in the trial were

included in the analysis.

Inadequate: Less than 90% of those randomised in to the trial

were included in the analysis.

Unclear: It is not clear how many people were originally ran-

domised into the trial or analysed.

6. DATA ANALYSIS

The protocol stated that we would only include the results for

CSOM participants where available, for studies that also enrolled

people with otitis externa, draining surgical cavities or acute otitis

media. However, we only did so if the authors reported stratifying

randomisation by diagnosis. Where information was not reported

regarding whether alternative diagnostic groups were stratified at

randomisation, we included all participants (groups may be un-

balanced, and decisions by trialists to report subgroups may have

been linked to trend).

P O T E N T I A L C O N F L I C T O F

I N T E R E S T

None known.

A C K N O W L E D G E M E N T S

The authors wish to thank Professor Paul Garner of the Cochrane

Infectious Diseases Group, Liverpool School of Tropical Medicine,

for his advice and support, and Miss Gemma Healy and Carolyn

Doree of the Cochrane ENT Disorders group for their help with

the searches.

S O U R C E S O F S U P P O R T

External sources of support

• Cochrane Ear, Nose and Throat Disorders Group UK

• Department for International Development UK

Internal sources of support

• Liverpool School of Tropical Medicine UK

• Cochrane Infectious Diseases Group UK

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∗Indicates the major publication for the study



T A B L E S

Characteristics of included studies

Study Browning 1983

Methods Randomised controlled trial

Participants See Table 03

75 adults over 16 years old, with active chronic otitis media randomised; 51 analysed.

19/51 (37%) analysed participants had previously undergone modified radical mastoidectomy - results were

not presented separately; all participants are included in this review.

Interventions See Table 04

1) Systemic non-quinolone antibiotics: oral cephalexin, flucloxacillin, cloxacillin or amoxicillin, 1-2g/day.

2) Topical non-quinolone antibiotic eardrops: chloramphenicol or gentamicin, 3 or 4 times daily, respectively.

3) Weekly insufflation of topical antiseptics (boric acid and iodine powder) after aural toilet.

Duration (all treatments):

4 weeks.

Aural toilet (all groups; confirmed by trial authors, personal correspondence):

weekly aural toilet by otologist, using microscopic vision and suction aspiration when necessary.

Participants with Pseudomonas species were randomised to topical antibiotic or antiseptics only (groups 2

or 3).

Choice of antibiotics depended on sensitivity of bacteria isolated at baseline.

Outcomes See Table 05

Review outcomes assessed:

1) CSOM resolution/failure (persistent discharge at 2 to 4 weeks).

Notes Setting: Secondary referrals at department of otolaryngology, Glasgow Royal Infirmary.

Location: Glasgow, UK.

Trial in other CSOM reviews: topical antibiotics.

Allocation concealment B – Unclear

Study Esposito 1990



60 adults, aged 18 or older, with CSOM in the acute stage were included (20 per group).


1) Systemic quinolone: oral ciprofloxacin 250mg

2) Systemic + topical quinolone: oral ciprofloxacin 250mg + ciprofloxacin eardrops 250 micrograms/mL

3) Topical quinolone: ciprofloxacin eardrops, 250 micrograms/mL

All treatment:

Twice daily for 5-10 days.



Characteristics of included studies (Continued )



1) CSOM resolution/failure (persistent discharge up to 4 weeks)

The results reported appear to be for 24 hours post-treatment (i.e. day 6-11); all those cured confirmed their

status 2 weeks later.

** 2) Improvement in hearing threshold **

(Reported negative statement for no ototoxicity only)

3) Adverse events (including assessment of ototoxicity)

* Outcomes not included in this review were also assessed - see table 05 *

Notes Setting: not reported.

Location: Italy

Sources of support: ciprofloxacin tablets and powder were provided by Bayer Italia Spa, Milan, Italy.


Study Esposito 1992



60 adults aged 18-65 years, with CSOM in the acute stage, with perforation of the tympanic membrane,

were included (30 per group).


1) Systemic non-quinolone antibiotic: intramuscular gentamicin sulfate 80mg (injectable vials)

2) Topical quinolone antibiotic: ciprofloxacin hydrochloride eardrops (250 micrograms/mL)

Both treatments:

Twice daily for 5-10 days.



1) CSOM resolution/failure (persistent discharge up to and after 4 weeks)

The results reported appear to be for 12 hours after 5-10 days treatment; all those cured confirmed their

status 2 and 3 weeks later (no relapses observed).





Notes Setting: not reported.

Location: Italy

Sources of support:

ciprofloxacin powder was provided by Bayer Italia Spa, Milan, Italy;

gentamicin injectable vials were provided by Schering Plough, Milan, Italy.





Study Mira 1992



248 randomised participants (aged 14-79 years) with recurrence of simple CSOM (n=196) or suppuration

following mastoidectomy (26) or tympanoplasty (26).

Results were not analysed by diagnosis separately (although baseline numbers were given for diagnoses by

treatment).


1) Systemic non-quinolone + topical placebo: intramuscular ceftizoxime 1g + topical saline solution

2) Systemic + topical non-quinolone antibiotic: intramuscular ceftizoxime 1g + topical ceftizoxime 2g in

saline solution

All treatments: twice daily for 7 days.

Aural toilet (both groups): aspiration of local secretions before 1st dose only.



** 1) CSOM resolution/failure (persistent discharge up to 3 weeks).

Reported symptom severity scores (including degree of otorrhoea) at days 3, 7 and 21, but no numerator or

indication of variation. **

2) Adverse events


Notes Setting: multi-centre study at the University of Pavia ENT clinic plus 10 hospital ENT departments.

Location: 11 sites in Italy

Study time-period: 3 month enrolment period.


Study Papastavros 1989


Crossover design - an unspecified number of participants who failed on the initially assigned treatment

group were transferred to the alternative group as new cases. Pre- and post-crossover data were not presented

separately.

Equivalence design and analysis.

Participants 90 patients (aged 11-79) contributing 119 ears with CSOM for 6 months to 40 years were included.

Includes participants with atticoantral and tubotympanic disease - results for clinical cure were presented

separately in the trial report, but randomisation was not described as stratified by diagnosis, so all cases are

included in this review.

Also includes participants with other symptoms or complications, including a positive fistular sign, and 4

had previously undergone mastoidectomy - data and results not presented separately.

6 further high risk complicated cases were included in the systemic antibiotics group without randomisation

- results not presented separately.


1) Systemic antibiotic: various oral or intravenous antibiotics (includes quinolones and non-quinolones) 2-

3 times daily; choice based on bacterial culture and in vitro sensitivity results.




2) Topical antiseptics: hydrogen peroxide drops or borax powder; choice determined at random.

Duration: mean 20.5 days (21.4 days systemic antibiotics; 19.2 days topical antiseptics) - planned for 10-20

days depending on outcome at 10 days.

Aural toilet (both groups): Toileting and debridement of the ear with suction as necessary, at regular visits.



1) CSOM resolution/failure (persistent discharge at 2 to 4 weeks).

Unclear if results are for after 10 days or 2 to 3 weeks treatment.

** 2) Adverse events (no results reported)**


Notes Location: Greece?

All participants were white; 33 came from rural areas and 57 from a large urban centre.

Setting: Not reported - appears to be hospital based.

Allocation concealment C – Inadequate

Study Povedano 1995



60 adults (aged 18-65), with chronic otorrhoea in the active phase, were randomised and analysed (30 per

treatment group).


1) Systemic quinolone antibiotic: oral ciprofloxacin, 500mg

2) Topical quinolone antibiotic: ciprofloxacin in saline solution eardrops (250 microgram/mL)

Both groups: twice daily for 10 days.



1) CSOM resolution/failure (Persistent discharge at 2 to 4 weeks)

Outcome was assessed at the end of 10 days treatment; included in the 2 to 4 week results for this review.


Notes Setting: Appears to be hospital based

Location: Spain (Cordoba)?


Study Supiyaphun 2000



80 randomised participants, over 15 years old (range was 15-78), with purulent or mucopurulent otorrhoea,

and central tympanic membrane perforation for longer than 21 days; 79 analysed (89 ears).


1) Systemic + topical non-quinolones: oral amoxicillin + topical chloramphenicol; both 3 times daily.

2) Systemic placebo + topical quinolone: oral placebo 3 times daily + topical ofloxacin twice daily




Duration (both groups): 2 weeks

Aural toilet (both groups): performed on Day 0 only.



1) CSOM resolution/failure (persistent discharge at 2 to 4 weeks)

2) Improvement in hearing threshold



Notes Setting: Outpatient service of the ENT department of Chulalongkorn University Hospital.

Location: Bangkok, Thailand.

Recruitment period: September 1996 - February 1998.

Study funding: supported by Daiichi Pharmaceutical (Thailand) Ltd.


Study Yuen 1994



60 adults (aged 18-70) with active CSOM with central perforation recruited; 56 analysed.


1) Systemic non-quinolone antibiotics: oral amoxicillin-clavulanic acid (Augmentin), 375mg

2) Topical quinolone: ofloxacin eardrops 0.3%

Both treatments: 3 times daily, for 1 week.

Aural toilet (both arms):

Suction cleaning before first dose.



1) CSOM resolution/failure (persistent discharge at 2 to 4 weeks)

** 2) Healing of the tympanic membrane

(Reported perforation size at baseline only) **

** 3) Improvement in hearing threshold

Reported summary statement only **

4) Adverse events


Notes Setting: Otorhinolaryngology outpatient clinic, University of Hong Kong, Queen Mary Hospital.

Location: Hong Kong (all participants were oriental).

Recruitment period: October 1991- February 1993.

Sources of support: study supported in part by a grant from the Committee on Research and Conference

Grants of the University of Hong Kong.

Allocation concealment A – Adequate



Study de Miguel 1999



125 participants (aged 6-83) with chronic otorrhoea (25 per treatment group); 100 included in this review

(4/5 treatment groups)

Includes four diagnostic subgroups - results not presented separately:

1) Simple chronic otitis media (n=45);

2) Osteitic chronic otitis media (with tympanosclerosis or chronic granulomatosis) (n=32);

3) Cholesteatomatous chronic otitis media (n=17);

4) Surgically operated hearing (n=31).


1) Systemic quinolone: oral ciprofloxacin 500mg

2) Systemic + topical quinolone: oral ciprofloxacin 500mg + topical 0.2% ciprofloxacin eardrops

3) Topical quinolone: 0.2% ciprofloxacin eardrops

4) Topical quinolone: 0.5% ciprofloxacin eardrops

* Other comparison not included in this review (25 participants): *

* 5) Topical non-quinolone antibiotic + steroid: Polymyxin B, neomycin + hydrocortisone eardrops *

Dose and frequency:

Oral tablets (groups 1-2): 500mg twice daily

Topical drops (groups 2-5): 3 drops 3 times daily

All treatments: 7 days with aspiration once (before treatment).



1) CSOM resolution/failure (persistent discharge)

Unclear whether the outcome reported is for day 8 or 15.





Notes Setting: Not reported (hospital/clinic?).

Location: Gran Canaria.

Study time period: Conducted over a 2-year period.

Article in Spanish.

Trial in other CSOM reviews: steroids.


* Not included under any treatments/outcomes specified for this review *

** Measured but not reported results **

Characteristics of excluded studies

Study Reason for exclusion

Adler 2000 PARTICIPANTS



Participants had acute otitis media with effusion, with no perforation of the tympanic membrane.

INTERVENTION

No participants received topical treatment (systemic antibiotics only).

Akisada 1997 INTERVENTION

No participants received topical treatment (oral antibiotics only).

Anon 1970a ALLOCATION

(Trial 1 of 2 reported in the paper): Included participants with chronic otorrhoea, but was not a randomised

controlled trial (no comparator group).

Anon 1970b PARTICIPANTS

(Trial 2 of 2 reported in the paper): Randomised controlled trial for participants with acute otitis media only.

Arguedas 1994 ALLOCATION

Participants were not randomised.

INTERVENTION:

No topical antimicrobial treatments were used (systemic antibiotics only).

Aslan 1998 ALLOCATION

Participants were divided into two groups, but allocation not described as randomised.

INTERVENTION

Both groups received topical antibiotic; no participants were allocated systemic treatment.

Baba 1982 ALLOCATION

Not a randomised controlled trial (no comparator group).

INTERVENTION

No participants received topical treatment (intravenous antibiotics only).

Baba 1982a INTERVENTION

No participants received topical treatment (oral antibiotics only).

Baba 1984 INTERVENTION

No participants received topical treatment (systemic treatments only).

Baba 1995 INTERVENTION

No participants received topical treatment (oral treatments only).

Blekher 1967 ALLOCATION

No mention of how the decision was taken to assign individual participants to different treatment groups.

Block 2000 PARTICIPANTS

Participants had acute otitis media for one week or less, without tympanic membrane perforation.

INTERVENTION

No participants were allocated topical treatment (systemic antibiotics only).

Brook 2001 PARTICIPANTS

Participants suffered from recurrent otitis media, not chronic suppurative otitis media.

INTERVENTION

Participants received oral antibiotics or no treatment - no participants were allocated topical treatment.

Browning 1983b ALLOCATION

Participants were not described as randomised.

INTERVENTION

No topical treatments were allocated (systemic antibiotics only).

Browning 1984 ALLOCATION

Editorial; not a randomised controlled trial.

Browning 1988 (INTERVENTION)

For steroids review (topical gentamicin-hydrocortisone + steroid versus placebo).

Chaput 1982 PARTICIPANTS

Participants had acute otitis media, not chronic suppurative otitis media.



INTERVENTION


Clayton 1990 (INTERVENTION)

For topical antibiotics review (topical antibiotic versus antiseptic; no systemic treatment).

Coates 2002 This is an editorial, not a randomised controlled trial.

Coates 2003 ALLOCATION

Not a randomised controlled trial - paper discusses 2 studies; 1 RCT (Couzos 2003, for Steroids review) and

a controlled clinical trial.

Colletti 1983 ALLOCATION

Not a randomised controlled trial - no comparator group.

INTERVENTION

All participants received intramuscular ribostamycin - no topical treatment group.

Connolly 1997 (INTERVENTION)

For review on delivery methods (compares alternative delivery methods of topical neomycin sulphate +

dexamethasone (Otomize): drops versus spray).

Cooke 1974 INTERVENTION

No participants were allocated topical treatment (given ear toilet with or without systemic (oral) antibiotics

only).

Couzos 2003 (INTERVENTION)

For steroids review (topical ciprofloxacin versus topical framycetin, gramicidin and dexamethasone

(Sofradex)).

Cronin 1974 ALLOCATION

Participants were not described as randomised.

Crowther 1991 (INTERVENTION)

For steroids review (topical antibiotic-steroid, gentamicin-hydrocortisone, versus topical steroid, betametha-

sone).

Damoiseaux 2004 This is a letter regarding treatment of acute otitis media, not a randomised controlled trial for CSOM

treatment.

Deguchi 1985 ALLOCATION

’Double blind study’ described in part of this paper does not appear to be a randomised controlled trial.

Deguchi 1986 ALLOCATION

Not a randomised controlled trial - 5 references described within the paper, one of which is apparently a

double-blind test, but further information not available.

Deguchi 1992 Review of several MIC studies, one of which is a phase III double-blind study, but reference not provided to

confirm eligibility.

Di Brino 1967 INTERVENTION

No participants were allocated topical treatments (oral antibiotics only).

Eason 1986 (INTERVENTION)

For other reviews instead: aural toilet, antiseptics, and steroids (comparisons are: no treatment; aural toilet

alone; aural toilet + topical boric acid; aural toilet + topical Sofradex (antibiotic+steroid); aural toilet + topical

Sofradex + oral clindamycin antibiotic).

Federspil 1969 ALLOCATION

Not a randomised controlled trial - topical or systemic gentamicin administered to a series of unselected

participants, with choice of allocation usually based on in vitro sensitivity tests.

Fliss 1990 INTERVENTION

No participants received topical antimicrobial agents (allocated 1 of 2 different systemic antibiotics or no

treatment).

Fontanel 1998 ALLOCATION



Not a randomised controlled trial.

Foshee 1992 PARTICIPANTS

Two trials reported in this one article. In both trials, participants had acute otitis media with effusion, not

chronic suppurative otitis media.

INTERVENTION

Participants were not allocated topical treatments in either trial (oral antibiotics only).

Fradis 1997 (INTERVENTION)

For topical antibiotics review (quinolone versus non-quinolone versus antiseptic; all topical).

Garcia-Rodriguez 93a ALLOCATION

Participants divided into two treatment groups but allocation was not described as randomised.

INTERVENTION

Participants were allocated topical antibiotics only (0.2% or 0.5% ciprofloxacin drops; no systemic treatment

group).

Garcia-Rodriguez 93b ALLOCATION

Participants divided into three treatment groups (oral and/or topical ciprofloxacin) but allocation was not

described as randomised.

Gasmanne 1972 (INTERVENTION)

For systemic antibiotics review? Comparisons were oral Bactrim or Ledermycin - no topical treatment group.

Ghosh 2001 This is a review of studies assessing oral antibiotics versus placebo for acute otitis media, not a trial for CSOM.

Gyde 1978 (INTERVENTION)

For topical antibiotics review (comparisons between topical non-quinolone antibiotics; no systemic treatment

group).


For topical antibiotics review (comparisons between topical non-quinolone antibiotics; no systemic treatment

group).


For steroids review (comparisons: topical non-quinolone antibiotic (gentamicin) versus topical non-

quinolone antibiotic+steroid (colistin, neomycin + hydrocortisone)).

Halsted 1967 PARTICIPANTS

Participants had acute otitis media, without a ruptured tympanic membrane, not chronic suppurative otitis

media.

INTERVENTION

No participants were allocated topical treatment (oral antibiotics or placebo only).

Howard 1976 PARTICIPANTS

Participants had acute otitis media, not chronic suppurative otitis media.

INTERVENTION


Howie 1971 PARTICIPANTS

Participants had recurrent acute otitis media with presence of middle ear fluid.

INTERVENTION

No participants were allocated topical treatments (oral antibiotic only).


Participants had acute otitis media with the presence of middle ear fluid.

INTERVENTION

No participants were allocated topical treatments (oral only).


Participants had acute or recurrent acute otitis media.

INTERVENTION




Indudharan 1997 (INTERVENTION)

For Steroids review: comparisons were topical gentamicin (antibiotic) versus gentamicin-betamethasone

(antibiotic-steroid) drops.

Jang 2004 ALLOCATION

Participants received topical vancomycin or gentamicin drops but allocation was not described as randomised.

Jaya 2003 (INTERVENTION)

For topical antibiotics review (topical quinolone antibiotic versus antiseptic; no systemic treatment groups).

John 1983 PARTICIPANTS

Participants were not described as having chronic suppurative otitis media.

INTERVENTION

Participants were randomised to oral antibiotic syrups; no participants received topical treatments.

Johnston 2003 (INTERVENTION)

(Unpublished trial) For steroids review - comparisons are: non-quinolone antibiotic + steroid (Otomize TM

spray; dexamethasone 0.1%, neomycin sulphate 3250 units/ml), with antiseptic (glacial acetic acid 2%)

versus antiseptic (Earcalm TM Spray; glacial acetic acid 2%).

Kaga 1997 INTERVENTION


Kantawala 1976 ALLOCATION

Treatment allocation not described as random (cases were selected at random, but unclear how control group

was selected).

INTERVENTION

Trial tests a mucolytic agent, Acetylcysteine; no comparisons with topical antibiotics or topical versus systemic

treatment.

Karabaev 1997 INTERVENTION

All participants received oral antioxidants - no topical treatment or comparator drug.

Kasemsuwan 1997 (INTERVENTION)

For topical antibiotics review (topical quinolone versus placebo; no systemic treatment groups).

Kashiwamura 2004 ALLOCATION

Not a randomised controlled trial - no comparator group.

INTERVENTION

No antibiotic group (topical antiseptic only).

Kawamura 1985 INTERVENTION


Kaygusuz 2002 (INTERVENTION)

For topical antibiotics and steroids reviews (topical quinolone versus topical non-quinolone, both with and

without steroids; no systemic treatment groups).

Khanna 2000 ALLOCATION

Quasi-randomised trial.

INTERVENTION

No topical eardrops were prescribed except in participants with fungal infections.

Kilcoyne 1973 ALLOCATION

Not a randomised controlled trial - no comparator treatment group (topical gentamicin hydrocortisone only).

Kiris 1998 INTERVENTION

Method of treatment delivery and aspiration daily or once only are compared, and not the actual treatment:

daily topical ciprofloxacin following aspiration administered by clinic personnel at the clinic, versus topical

quinolone self-administered at home after the first treatment with aspiration at the clinic only.

Kriukov 1996 Study 1 of 2:

ALLOCATION



Not described as a randomised controlled trial - oral rovamycin compared to normal standard treatment.

Study 2 of 2:

ALLOCATION

Treatment allocation not described as randomised.

INTERVENTION

Bacterial study of oral amoxyclav compared to alternative oral treatments for a range of inflammatory ENT

infections.

Lancaster 1999 ALLOCATION

Not a randomised controlled trial (all participants received topical gentamicin with comparisons made

between their diseased and non-diseased ears before and after treatment).

Lancaster 2003 ALLOCATION

Participants received antibiotic drops or spray, but treatment allocation was not described as randomised.

INTERVENTION

No participants were allocated systemic treatment.

Legent 1994 INTERVENTION


Leiberman 1989 (INTERVENTION)

For systemic antibiotics review - participants were randomised to intravenous Mezlocillin or Ceftazidime;

no topical antimicrobials were used during the study.

Lildholdt 1986 INTERVENTION

For surgery review. No participants were allocated topical treatments (systemic antibiotics versus no drug

treatment).

Linder 1997 Comment on two trials (one on otitis media with effusion, and Smith 1996 trial); not a randomised controlled

trial itself.

Lorente 1995 (INTERVENTION)

For topical antibiotics review (topical quinolone versus topical non-quinolone; no systemic treatment groups).

Macfadyen 2005a (INTERVENTION)

For topical antibiotics review (topical quinolone versus topical antiseptic; no systemic treatment groups).

McKelvie 1975 (INTERVENTION)

For probable inclusion in topical antibiotics review - awaiting full assessment. Comparisons were topical

gentamicin drops versus placebo.

Mendonca 1969 ALLOCATION

Not a randomised controlled trial - no comparator treatment group (topical gentamicin only).

Merifield 1993 ALLOCATION

Participants were categorised into treatment groups, but not described as randomised.

PARTICIPANTS

Participants had tympanostomy tubes accompanied by chronic suppurative otitis media.

INTERVENTION

All participants were allocated eardrops (antibiotic or antibiotic-steroid combinations); no systemic treatment

was tested.

Mesure 1973 (INTERVENTION)

For systemic antibiotics review - participants were randomised to systemic Bactrim or demethylchlortetra-

cycline; no topical treatment groups.

Miro 2000 (INTERVENTION)

For steroids review (comparisons: topical quinolone, ciprofloxacin, versus topical non-quinolone antibiotic

and steroid, polymyxin B, neomycin and hydrocortisone.

Miskovska 2004 PARTICIPANTS

Participants had acute otitis media, not CSOM.

INTERVENTION



No topical treatment group; participants received systemic penicillin, surgery, or both.

Moreno Martínez 1988 PARTICIPANTS

Participants treated for a range of ENT infections, including otitis media with fever, not CSOM.

INTERVENTION

No topical treatment groups (systemic only).

Nawasreh 2001 (INTERVENTION)

No systemic treatment groups.

Possibly for topical antibiotics review (topical quinolone versus topical non-quinolone), but seeking clarifi-

cation from authors whether this is the same trial as Tutkun 1995.

Occhiuzzi 1972 INTERVENTION

For possible inclusion in systemic antibiotics review. Both groups of participants received intramuscular

treatment (no topical treatment groups).

Ott 2001 (ALLOCATION)

Not a randomised controlled trial (tutorial).

Picozzi 1983 (INTERVENTION)

For steroids review (comparisons: topical non-quinolone antibiotic + steroid, gentamicin + hydrocortisone,

versus placebo; aural toilet both groups).

Picozzi 1984 (INTERVENTION)

For steroids review (comparisons: topical non-quinolone antibiotic + steroid, gentamicin + hydrocortisone,

versus topical gentamicin + hydrocortisone + systemic non-quinolone antibiotic, metronidazole; aural toilet

both groups).

Pugliese 1972 PARTICIPANTS

Participants had acute otitis media.

INTERVENTION

No participants were allocated topical treatment (oral antibiotics only).

Quick 1975 PARTICIPANTS

Participants suffered from a range of ENT disorders including acute otitis media, but none described to have


INTERVENTION

No participants were allocated topical treatments (systemic antibiotics only)

Rostein 1978 INTERVENTION

No topical treatment group - alll participants received oral sulfamethoxazol-trimethoprime.

Roy 2003 (INTERVENTION)

(Unpublished trial) For steroids review - comparisons are topical quinolone, ciprofloxacin ear drops, versus

topical non-quinolone + steroid, Gentisone HC (hydrocortisone) ear drops.

Salzberg 1972 ALLOCATION

Not described as randomised.

PARTICIPANTS

Includes a range of upper respiratory tract infections, not specific to CSOM.

INTERVENTION


Sambe 1977 INTERVENTION

For possible inclusion in systemic antibiotics review. Participants were allocated systemic Pipdemic acid or

Aminobenzyl penicillin; no topical treatment groups.

Schaad 1986 INTERVENTION

No topical treatment group - participants were allocated oral bacterial lysate or placebo.

Schechkin 1978 ALLOCATION

Not a randomised controlled trial (no comparator group).



Shah 2000 Not a randomised controlled trial - analyses of bacteriology and drug sensitivity only; no treatment arm or

effectiveness analyses of participants.

Shenderey 1985 PARTICIPANTS

Participants suffered from acute respiratory tract infections, including otitis media; none described to have


INTERVENTION


Smith 1996 (INTERVENTION)

For possible inclusion in steroids review. (Comparisons: dry mopping alone; versus dry mopping plus topical

non-quinolone antibiotic + steroid, framycetin, gramicidin + dexamethasone (Sofradex) plus systemic non-

quinolone antibiotic, oral amoxicillin; versus no specific treatment).

Somekh 2000 INTERVENTION

No participants were allocated topical treatments (both groups received intravenous antibiotics).

Stechenberg 1976 PARTICIPANTS

Participants had acute otitis media, not chronic otitis media.

INTERVENTION

No participants were allocated topical treatments (systemic antibiotics only).

Sugiyama 1981 ALLOCATION

Participants were divided into two groups (receiving oral or topical antibiotic), but not described as ran-

domised.

Supiyaphun 1995 ALLOCATION


INTERVENTION

All participants received topical 0.3% ofloxacin, with no comparator group.

Tachibana 1986 INTERVENTION

No participants were allocated topical treatment (administered intravenously in both groups).

Tong 1996 (INTERVENTION)

For steroid review (comparisons: topical quinolone, ofloxacin, versus topical non-quinolone antibiotic +

steroid, neomycin-polymyxin B-hydrocortisone drops).

Tong 2002 (INTERVENTION)

For surgery review - results before surgery were not provided.

Tutkun 1995 (INTERVENTION)

For topical antibiotics review (topical quinolone versus topical non-quinolone; no systemic treatment groups).

Van de Heyning 1988 ALLOCATION


INTERVENTION

All participants received oral ciprofloxacin, with no comparison group.

Verhoeff 2003 INTERVENTION

No topical treatment group (comparisons were systemic antibiotic versus placebo).

Wilde 1995 INTERVENTION

Mode of delivery of treatment under investigation, not actual treatment (regular antibiotic-steroid ointment

(Tri-Adcortyl) dressing versus Tri-Adcortyl ointment instilled into the ear once only).

Willis 1979 PARTICIPANTS

The trial described within this discussion paper is for colorectal and bowel surgery, not otitis media.

Zbären 1983 INTERVENTION

Only systemic antibiotics were given; no topical treatment group.

van Hasselt 1997 (INTERVENTION)



Characteristics of excluded studies (Continued )

For topical antibiotics review (topical quinolone antibiotic versus non-quinolone antibiotic versus antiseptic;

all topical - no systemic treatment groups).


For topical antibiotics review (topical quinolone antibiotic versus topical non-quinolone antibiotic, using 2

treatment regimens for each; no systemic treatment groups).


For topical antibiotics review (topical quinolone versus topical antiseptic versus placebo; no systemic treatment

groups).



A D D I T I O N A L T A B L E S

Table 01. Methodological quality of included studies

Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up

Browning 1983 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 (i.e. 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.

de Miguel 1999 Unclear


described as random, but

randomisation method was

not stated.

Did not discuss whether

randomisation was stratified

by the 4 diagnostic groups

Unclear

Allocation concealment not

reported - nor was blinding.

Unclear (partly comparable)

Baseline characteristics not

reported for each group,

except infective organism

(which was comparable

except fewer Pseudomonas

aeruginosa isolated for the

ciprofloxacin 0.2% group).

Unclear

Blinding not mentioned.

Adequate

No withdrawal was reported.

125 participants were

reported as entered into the

trial and analysed (25 per

group - i.e. 100 for this

review).

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Table 01. Methodological quality of included studies (Continued )


(and results not reported

separately in trial report).

The distribution of the 4

diagnostic groups was not

reported.

Esposito 1990 Unclear




not stated.

Unclear



Mostly

Groups comparable at

baseline for age and sex,

but the group receiving

oral ciprofloxacin only

had a higher prevalence of

Pseudomonas and hence

lower number of gram-

positive cocci.

Unclear


Adequate




trial and were analysed (20

per group).

Esposito 1992 Unclear




not stated.

Unclear



Yes

Balanced for age and sex.

No other baseline characters

were reported.

Unclear


Adequate




trial and were analysed (30

per group).

Mira 1992 Adequate

Participants were

randomised according to

blocked randomisation

tables (block size 4), one for

each centre.

Unclear


not reported - but trial was

reported to be single blind.

Yes


baseline for number of

participants, age, sex,

diagnosis, presence and

severity of symptoms, and

bacteriology.

(The slight higher number

of tympanoplasty and

mastoidectomy participants

on systemic+topical

treatment, was not

statistically significant).

Single blind

Described as single blind

but no further information

provided.

Unclear

1/248 (0.4%) participants

(who received systemic+

topical therapy) dropped

out of the study before

completing treatment,

and failed to attend the

scheduled visits.

BUT not reported numbers

analysed (for cultures

taken or symptom scores;

or standard deviation

for symptom scores), to

confirm whether adequate

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Papastavros 1989 Inadequate


described as random (after

obtaining culture results),

but randomisation method

was not stated.

Randomisation does not

appear to be stratified by the

different diagnostic groups.

6 participants considered at

high risk of complication

were all allocated systemic

treatment for ethical reasons,

and not randomised.

Choice of antibiotic

depended on bacterial

cultures and in vitro

sensitivity;

Choice of antiseptic was

determined at random.

Unclear



Mostly but not for morbidity

Distribution of cases were

balanced between systemic

and topical modalities for

age, sex, socioeconomic

class, duration of disease and

type of chronic otitis (tubo-

tympanic or atticoantral).

But morbidity was higher

in the systemic antibiotic

group, due to non-random

allocation of 6 complicated

to this group.

The distribution of other

complications or previous

surgery was not reported.

Unclear


Adequate


90 participants with 119

ears (71 antibiotics, 48

antiseptics) were reported as

entered into the trial and

were analysed.

Povedano 1995 Unclear




not stated.

Unclear



Yes


baseline for age, sex and

bacteriology.

Unclear


Adequate

All participants were

reported to have completed

the study, with no dropouts.

Supiyaphun 2000 Unclear




not stated.

Unclear


not mentioned - but

’investigator-blinded’ trial.

Yes


baseline for demographic

(age, sex) and disease-related

characteristics (laterality of

infection, size, duration, and

cause of perforation, and

pathogenic organisms).

Investigator blinded

Double dummy for oral

medication - placebo oral

capsules for the ofloxacin

arm, were the same size and

colour as amoxicillin 500mg

capsules.

Unclear

1.25% dropout: 1/80

participants (participant

received topical ofloxacin)

missed visits and therefore

excluded from the study.

But results were only

presented as percentage of

ears, not actual numbers or

totals; rates reported do not

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equate to whole ears when

using total numbers of ears.

Therefore unclear whether

adequate numbers were

included in the analysis.

Yuen 1994 Adequate

Participants were

randomised into 2 groups

by drawing concealed

envelopes.

Adequate

Envelopes with treatment

groups were concealed.

Mostly


baseline for perforation

size, mucosal inflammation,

nature of discharge

(more purulent cases

for Augmentin, but not

statistically significant), and

bacteriology (but slightly

lower rate of bacteria isolated

in ofloxacin (62%) than

Augmentin (70%)).

Ofloxacin had better

overall in vitro antibiotic

susceptibility results than

Augmentin, due to its better

activity against Pseudomonas

species.

Unclear


Adequate

7% dropout rate: 4/60

participants excluded from

the analysis (3/30 oral

Augmentin, 1/30 topical

ofloxacin).

Reasons for exclusion:

3 defaulted follow-up (2

Augmentin, 1 ofloxacin)

1 did not complete

the course of treatment

(Augmentin) due to gastric

upset.

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Table 02. Bilateral Disease: Numbers for Ears vs Participants

Study ID # of particpants # of ears % bilateral cases

Handling bilat

cases Results: pt or ears?

Browning 1983 75 randomised -

all treatments; not

reported by group.

51 analysed:

13 systemic

antibiotics

18 topical

antibiotics

20 topical

antiseptics

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

de Miguel 1999 Total: 125 (25 per

group; i.e. 100 for

this review)

Not reported? Not reported? Not reported? Participants?

Esposito 1990 Total: 60 adults

(20 per treatment

group)

Not reported Not reported Unclear - reported

at participant level.

Participants

Esposito 1992 Total: 60 adults

(30 per treatment

group)



Participants

Mira 1992 Randomised

participants:

248 all diagnoses:

(120 systemic

ceftizoxime, 128

systemic+topical

ceftizoxime)

196 simple,

uncomplicated

CSOM:

(99 systemic, 97

systemic+topical)

26 suppuration

following

tympanoplasty:

(10 systemic; 16

systemic+topical)

26 suppuration

following

mastoidectomy:


at participant level,

but reported scores

without numbers.

Participants



Table 02. Bilateral Disease: Numbers for Ears vs Participants (Continued )


Handling bilat


(11 systemic; 15

systemic+topical)

Results were not

presented separately

by diagnosis.

Analysed - numbers

not reported;

only 1 drop-out

was reported (on

systemic+topical

ceftizoxime).

Papastavros 1989 Analysed

participants:

90 total (not

reported by group).

Analysed ears:

119 total (68

tubotympanic; 51

atticoantral):

71 systemic

antibiotics:

(42 tubotympanic;

29 atticoantral)

48 topical

antiseptics:

(26 tubotympanic;

22 atticoantral);

(21 hydrogen

peroxide drops; 27

borax powder).

Total 29/90

(32.2%) (not

reported by group).

Analysed and

reported for

numbers of ears

separately.

Ears

Povedano 1995 Total: 60 adults (30

per group).

Not reported - same

as participants?

Not reported Unclear - reported

at participant

level, although

bacteriology for ears

matches number of

participants?

Participants? (For

clinical success).

Unclear for

bacteriology results.

Supiyaphun 2000 80 randomised

participants:

(40 oral amoxicillin

+ topical

chloramphenicol;

40 topical ofloxacin

drops).

79 analysed

participants:


+ topical

chloramphenicol;

39 topical ofloxacin

drops)

89 analysed ears:


+ topical

chloramphenicol;

44 topical

ofloxacin).

Analysed rates:

Total 10/79

(12.7%)

Oral amoxicillin

+ topical

chloramphenicol:

5/40 (12.5%)

Topical ofloxacin

drops: 5/39

(12.8%).

Unclear - results

were only presented

as percentage of

ears, not actual

numbers or totals;

but rates reported

do not equate to

whole ears when

using total numbers

of ears (sometimes

match number of

participants more

closely).

% ears but rates do

not equate to whole

ears.



Table 02. Bilateral Disease: Numbers for Ears vs Participants (Continued )


Handling bilat


Yuen 1994 60 recruited

participants:

(30 oral Augmentin;

30 topical

ofloxacin).

56 analysed

participants:

(27 oral Augmentin;

29 topical

ofloxacin).



Participants



Table 03. Participant eligibility criteria, including CSOM diagnostic criteria

Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease

duration Bacteriology?

Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

Browning 1983 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).

No

de Miguel 1999 Otorrhoea

diagnosed on

otoscopy under

microscopy - 4

subgroups:

a) Simple

chronic otitis

media - no

osteitic changes,

tympanosclerosis

or

cholesteatoma;

b) Osteitic

chronic otitis

media - with

changes to

the ossicular

chain and some

permanent

alterations in

the mucosa

(tympanosclero-

sis or chronic

Not reported Previous

antibiotic

treatment was

allowed, and had

been received

by 79/125 of

all randomised

participants

(63.2%).

Analgesics and

antipyretics

allowed during

the study.

Age ranged from

6-83 years.

Other eligibility

criteria:

None specified.

Not specified Indicated.

Unclear whether

required for

inclusion or not.

Yes: some

permanent

alterations in

the mucosa for

diagnostic group

b): “Osteitic”

chronic otitis

media.

a) 45 Simple

chronic otitis

media;

b) 32 “Osteitic”

chronic otitis

media (with

tympanosclerosis

or chronic

granulomatosis);

c) 17

Cholesteatoma-

tous chronic

otitis media;

d) 31 Post

surgery cases.

N = 125 (ie

all included

participants),

but only 100

included in

this review

(4 treatment

groups) -

No

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Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

granulomatosis);

c)

Cholesteatoma-

tous chronic

otitis media;

d) Post surgery

cases.

number per

treatment not

available.

Esposito 1990 Mild or

moderate

chronic

suppurative

otitis media in

the acute stage.

1)

Cholesteatoma

2) Mastoiditis

Inclusion criteria

- other:

1) Adults at least

18 years old

(mean age was

38)

2) Informed

participant

consent

Exclusion

criteria -

treatment related

1) History of

previous allergy

to quinolone

derivatives

No participants

took any other

drug during the

study.

63% (38/60)

had received

antibiotic

treatment for

at least 5 days

before study

treatment,

Not reported

other than

’chronic

suppurative

otitis media in

the acute stage’.

Indicated.

Unclear whether

required for

inclusion.

Bacteria was

isolated for all

participants

before treatment.

Not reported None specified

- see otitis

exclusions.

n/a

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

without

significant

improvement.

Exclusion -

other:

1) Pregnant

women

2) Younger than

18 years old

No participants

had any

underlying

diseases (such as

diabetes).

Esposito 1992 Mild or

moderate

chronic

suppurative

otitis media in

the acute stage,

with

perforation of

the tympanic

membrane, and

bacteriological

culture positive

for Pseudomonas

susceptible

to in vitro

ciprofloxacin

and gentamicin.

Diagnosis

according to

the following

1)

Cholesteatoma

2) Mastoiditis

Inclusion criteria

- other:

1) Adults at least

18 years old

(range was 18-

65, mean 39)

2) Informed

participant

consent

Exclusion criteria

- treatment

related:

1) History

of allergy to

quinolones or

aminoglycosides

No participants

took any other

drug during the

study.

Otitis media

lasted at least 3

years;

Purulent

otorrhoea

recurrent at least

once annually;

and

Resistant

episodes of

purulent

otorrhoea had

been constant

for at least 15

days.

Yes.

Bacteriological

culture positive

for Pseudomonas

susceptible

to in vitro

ciprofloxacin

and gentamicin

required for

study inclusion.

Not reported None specified

- see otitis

exclusions.

n/a

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

criteria:

1) Otitis media

had lasted at

least three years

2) Purulent

otorrhoea had

recurred at least

once annually

3) Resistant

episodes of

purulent

otorrhoea had

been constant

for at least 15

days.

67% (40/60) had

received previous

antibiotic

treatment for

5-10 days;

interrupted 1-

7 days before

study entry, after

no significant

improvement.

Exclusion

criteria - other:

1) Pregnant

women

2) Younger than

18 years

No participants

had any

underlying

diseases (such as

diabetes)

Mira 1992 Suppuration

following:

a) recurrence

(new acute

phase) of simple

CSOM

b)

tympanoplasty

c)

mastoidectomy

1) Otitis externa

2)

Cholesteatoma

Inclusion criteria

- other:

1) Age over 14

years (mean

(SD) was 42.6

(13.7); range 14-

79).

2) Informed

consent.

Exclusion criteria

- treatment

related:

1) Ascertained

Not specified Indicated.

Not required

for inclusion

- causative

organism

only isolated

in 145/248

(58.5%)

participants at

baseline.

Eradication of

isolated bacteria

reported (also by

Oedema severity

scores included

as an outcome.

a) 196 recurrent

simple CSOM

(99 systemic;

97 systemic+

topical)

b) 26

suppuration

following

tympanoplasty

(10 systemic;

16 systemic+

topical).

c) 26

No

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

or suspected

hypersensitivity

to

cephalosporins

and/or

penicillins

No other

antibiotics

were allowed

throughout the

study period,

but appropriate

drugs for

concomitant

diseases were

permitted.

Exclusion

criteria - other:

1) Concomitant

serious diseases

(neoplasia,

renal or hepatic

insufficiency)

2) Known

or suspected

pregnancy or

lactating.

pathogen) as an

outcome.

suppuration

following

mastoidectomy

(11 systemic;

15 systemic+

topical).

Papastavros

1989

Participants with

discharging ears.

A case of CSOM

must meet

either:

1) Persistent

drainage for at

1) Non-

suppurative cases

2) Cases of

questionable

chronicity

Inclusion criteria

- treatment

related:

1) All existing

medications were

discontinued

at least 3 days

Range 6

months (shortest

duration

accepted) to 40

years.

Indicated.

Clinical response

presented by

pathogen, and

bacteriological

response

reported.

Included in

definition

of clinical

response (colour,

oedema and

granulations/

polyps).

a) 68 persistent

tubo-tympanic

mucositis:

42 systemic

antibiotics,

26 topical

antiseptics;

Only for

tubotympanic

vs atticoantral

disease.

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

least the previous

6 months; or

2) Drainage at

1st visit and

history of at least

3 recurrences

during the

previous 12

months.

Classified as:

a) persistent

tubo-tympanic

mucositis

(simple chronic

mucositis)

b) atticoantral

disease

(cholesteatoma

and/or osteitis)

(Diagnosed

on clinical

examination;

later confirmed

on surgery for 65

who underwent

surgery).

Other findings

were:

Symptoms

including

otalgia,

headache,

tinnitus,

recurrent

true vertigo,

before drainage

for cultures and

5 days before

randomisation

and starting

study treatment

(started after

results of culture

were available).

Inclusion criteria

- other

1) Written

informed

consent

Age range was

11-79 years,

median 49.

All participants

were white, from

rural areas or

a large urban

centre.

Not reported

as an inclusion

criterion.

(37 had

simple chronic

mucositis

confirmed on

surgery).

b) 51 atticoantral

disease:

29 systemic

antibiotics,

22 topical

antiseptics;

(28 had

cholesteatoma

and/or osteitis

confirmed

on surgery -

cholesteatoma

was undiagnosed

pre-operatively

in 2 cases).

Other findings:

Around one

third of cases

had 1 or more

of: otalgia,

headache,

tinnitus,

recurrent

true vertigo,

dizziness and/or

a sensation of

imbalance.

About one sixth

of cases had a

positive fistula

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

dizziness and/or

a sensation of

imbalance.

Positive

fistula sign

demonstrable

after removing

discharge or

debris.

Previously

undergone

mastoidectomy.

Cases at high risk

of complication,

allocated

systemic

antibiotics (not

randomised).

sign.

4 participants

had previously

undergone a

mastoidectomy.

6 high risk

complicated

cases were

allocated

systemic

antibiotics.

Povedano 1995 Chronic

otorrhoea in the

active phase.

Not reported Inclusion criteria

- other:

1) Written

informed

consent

2) Adults (age

range was 18-65

years)

Exclusion criteria

- treatment

related:

1) Previous or

concurrent use

of any treatment

2) Previous or

suspected allergy

Not specified Yes.

Indicated

pre-and post

treatment

bacteriology,

and reported

as an outcome

measure.

All cases had

bacteria isolated

before treatment,

but not specified

as an inclusion

criteria.

Not reported None specified n/a

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

to quinolones

Exclusion

criteria - other:

1) Under 18

years old

2) Underlying

diseases, eg

diabetes,

cardiopathy, etc.

Supiyaphun

2000

Active chronic

otitis media

with purulent or

mucopurulent

otorrhoea,

and central

perforation of

the tympanic

membrane of

greater than 21

days duration.

1)

Cholesteatoma

or large aural

polyp in the

middle ear or

mastoid

2) History of ear

surgery within

the previous year

Inclusion criteria

- other:

1) Over 15 years

old (range was

15-78, mean

(SD) 33 (12.5))

Exclusion criteria

- treatment

related:

1) Therapy

with systemic

antibiotics or

any ototopical

agents within 2

weeks

2) Allergy to

penicillin, chlo-

ramphenicol,

or quinolone

antibiotics

Exclusion

criteria - other:

1) Pregnant or

lactating.

>21 days

duration

(perforation)

Indicated.

Baseline

bacteria and

bacteriological

outcome

reported but

not required for

inclusion.

10.1%

participants

(9/89; 9.1%

ofloxacin, 11.1%

amoxicillin+

chlorampheni-

col) had no

growth; 9

further cases

(10.1%) had

contamination.

Assessed on

microscopy at

baseline.

Improvement

in severity and

disappearance

of middle ear

inflammation

reported as an

outcome.

None specified n/a

Yuen 1994 Active chronic 1) Inclusion criteria Not specified Indicated. Severity of None specified n/a

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Study ID

CSOM

diagnosis

Otitis

exclusions

Other elig

criteria

Disease


Mucosal

appearance?

Other

diagnoses?

Other diags:

sep?

suppurative

otitis media

with central

perforation.

Cholesteatoma

2) Discharging

mastoid cavity

3) Large aural

polyp

4) Acute

traumatic

perforation

5) Acute otitis

media

6) Presence of a

grommet

7) History of

radiotherapy of

the temporal

bone

8) Otomycosis

- other

1) Adults (range

was 18-70 years,

median 35)

All participants

had no prior

antibiotic

treatment

for at least 1

week before

commencing

study treatment.

Exclusion

criteria - other:

None specified.

- but acute

otitis media was

an exclusion

criterion.

Not required for

inclusion.

Baseline

bacteriology was

reported:

Only 37/56

(66%) of

participants

had pathogens

found in baseline

cultures (62%

ofloxacin, 70%

Augmentin).

middle ear

mucosal

inflammation

reported at

baseline and as

an outcome.

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Table 04. Intervention regimens used

Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds

Systemic antibiotic vs topical antiseptic

Systemic non-quinolone daily vs topical antiseptic weekly

Browning 1983 1) Systemic non-

quinolone antibiotic:

oral cephalexin,

flucloxacillin,

cloxacillin or

amoxicillin (self-

treated).

3) Topical antiseptics:

insufflation of boric

acid and iodine powder

after aural toilet

(otologist treated).

Participants with

Pseudomonas species

were randomised only

to topical antibiotic

or antiseptic, not

systemic antibiotic due

to resistance.

Choice of antibiotics


of bacteria isolated at

baseline.

1) Systemic antibiotics:

oral (formulation not

specified).


insufflation of

antiseptic powder.


1-2g/day (self-treat)

3) 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.

Systemic quinolone & non-quinolone antibiotics vs topical antiseptic

Papastavros 1989 1) Systemic antibiotics

- choice of:

a) Intravenous non-

quinolones: piperacillin

(2), aztreonam

(Azactam) (12);

b) Oral non-

quinolones: amoxicillin


a) intravenous;

b-d) oral


a) Hydrogen peroxide:

instillation of drops

b) Borax: insufflation

of powder.


various doses, 2-3 times

daily.

a) Intravenous non-

quinolones: piperacillin

1000mg twice daily;

Azactam 500mg 3

times daily;

Mean duration: (overall

20.5 days)


21.4 days

(19.4 tubotympanic;

24.3 atticoantral)


19.2 days

Both groups (all

treatments):

Toileting and

debridement of the

ear with suction as

necessary, performed at

regular visits.

All existing medications

were discontinued

at least 3 days

before drainage for

cultures and 5 days

before randomisation

and starting study

treatment (started after

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Table 04. Intervention regimens used (Continued )


+ clavulanate (2),

erythromicin (2),

metronidazole (6),

sulfamethoxazole +

trimethoprim (29);

c) Oral quinolones:

ciprofloxacin (8);

d) Oral quinolone+

non-quinolones:

ciprofloxacin +

metronidazole (10);

Choice of antibiotic

depended on culture

and sensitivities

6 participants at high

risk of complications

were given systemic

antibiotics (not

randomised).

2) Topical antiseptics -

either:

a) Hydrogen peroxide

drops (21) or

b) Borax powder (27)

Choice of antiseptics

was random.

All treatments:

Modified according to

clinical response and

culture taken every c10

days.

Crossover: failures

on initial treatment

were transferred to the

alternative group as

new cases (numbers

b & d) Oral non-

quinolones:

Twice daily:

erythromycin 1000mg;

sulfamethoxazole

800mg + trimethoprim

160mg

3 times daily:

amoxicillin+clavulanate

625mg; metronidazole

500mg;

c & d) Oral quinolone:

ciprofloxacin 500mg

twice daily.

2) Antiseptics - not

reported.

(19.7 tubotympanic;

18.7 atticoantral)

Duration up to 2-

3 weeks: planned

to continue for 10

days before deemed

unsuccessful, or 10

additional days after

successful outcome.

Unsuccessful cases were

transferred to the other

treatment group or

released from the study.

results of culture were

available).

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not reported). Pre- and

post-crossover data

were not presented

separately.

Systemic antibiotics vs topical antibiotic eardrops:

Systemic non-quinolone vs topical non-quinolone

Browning 1983 1) Systemic antibiotic:

oral cephalexin,

flucloxacillin,

cloxacillin or

amoxicillin.

2) Topical antibiotic:

Chloramphenicol

(Chloromycetin), or

gentamicin (Genticin)

Participants with

Pseudomonas species

were randomised only

to topical antibiotic

or antiseptic, not

systemic antibiotic due

to resistance.

Choice of antibiotics


of bacteria isolated at

baseline.


oral (formulation not

specified)

2) Topical antibiotics:

eardrops


1-2g/day (not reported

by antibiotic)

2) Topical antibiotics:

a) Chloramphenicol:

1 or 2 drops, 3 times

daily;

b) gentamicin: 3 or 4

drops, 4 times daily.

All treatments:

4 weeks

All groups:

Weekly aural toilet

by otologist, using

microscopic vision

and suction aspiration

when necessary.

Not reported

Systemic non-quinolone vs topical quinolone

Esposito 1992 1) Systemic

non-quinolone:

intramuscular

gentamicin sulfate

(gentamicin injectable

vials provided by

1) Systemic

non-quinolone:

intramuscular

injectable vials 2)

Topical quinolone:

eardrop solution

1) Systemic non-

quinolone: 80mg

twice daily (according

to the manufacture’s

dosing suggestions)

2) Topical quinolone:

All treatment: 5-10

days (5 days initially;

if no cure after 5 days,

continued until cure

but not longer than 10

days total).

Not specified No participants

took any other drug

during the study. 67%

(40/60) had received

previous antibiotic

treatment for 5-10

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Schering Plough,

Milan, Italy) 2)

Topical quinolone:

ciprofloxacin

hydrochloride in saline

solution (ciprofloxacin

powder provided by

Bayer Italia Spa, Milan,

Italy)

250 micrograms/mL; 4

drops twice daily

days; interrupted 1-7

days before study entry

after no significant

improvement.

Yuen 1994 1) Systemic non-

quinolone: oral

amoxicillin-clavulanic

acid (Augmentin)


ofloxacin eardrops

1) Systemic: oral

Augmentin

2) Topical ofloxacin

eardrops

1) Systemic: 375mg

Augmentin

2) Topical: 0.3%

ofloxacin

Both treatments: 3

times daily

Both treatments:

1 week

Both groups:

Suction cleaning before

1st dose

All participants had

no prior antibiotic

treatment for at least 1

week before starting

study treatment.

Systemic quinolone vs topical quinolone

De Miguel 1999 1) Systemic: oral

ciprofloxacin

3) Topical:

ciprofloxacin 0.2%

4) Topical:

ciprofloxacin 0.5%

1) Systemic oral tablet

3) & 4) Topical eardrop

solution

1) Systemic: 500mg

twice daily (1 tablet

every 12 hours)

3) & 4) Topical 0.2%

& 0.5% ciprofloxacin:

3 drops 3 times daily

(c0.15mL every 8

hours)

All treatments:

7 days

All groups:

Aspiration before

starting treatment only.

Analgesics and

antipyretics allowed

during the study.

63.2% (79/125)

of all randomised

participants had

received previous

antibiotic treatment.

Esposito 1990 1) Systemic: oral

ciprofloxacin

3) Topical:

ciprofloxacin in saline

solution


3) Topical eardrop

solution

1) Systemic: 250mg

twice daily

3) Topical: 250

micrograms/mL, 3

drops twice daily

All treatments:

5-10 days (5 days

initially; if no cure after

5 days, continued until

cure but not longer

than 10 days total).

Not specified No participants took

any other drug during

the study.

63% (38/60) had

received antibiotic

treatment for at

least 5 days before

study treatment,

without significant

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Povedano 1995 1) Systemic: oral

ciprofloxacin

2) Topical:


solution

1) Systemic oral

(tablet?)

2) Topical eardrop

solution

1) Systemic: 500mg

twice daily (every 12

hours)

2) Topical: 250

microgram/mL (0.9%);

5 drops twice daily

(every 12 hours)

Both treatments:

10 days

Not specified No previous or

concurrent use of

any treatment was

allowed (reported as an

exclusion criterion);

washout period not

reported.

Systemic antibiotic alone vs systemic + topical antibiotic

Systemic non-quinolone vs systemic + topical non-quinolone

Mira 1992 1) Systemic antibiotic +

topical placebo:

intramuscular

ceftizoxime + topical

normal saline solution

2) Systemic + topical

antibiotic:

intramuscular

ceftizoxime + topical

ceftizoxime in saline

solution

All treatments:

Initial treatment by

specialist in the clinic;

thereafter by a relative

of the participant

following instruction.

Ceftizoxime vials

(intramuscular):

Eposerin R, Farmitalia.

Both groups:

Systemic:

intramuscular

Topical: eardrops

Systemic:

1) & 2): 2 g daily (1

vial containing 1g

Ceftizoxime every 12

hours).

Topical:

1) 4 ml normal saline

solution

2) 2g ceftizoxime in

4ml saline solution

Topical - both groups:

4ml twice daily (2ml

initially, using a

gradated syringe; the

remaining 2ml 3-5

minutes later).

Ear gauze applied after

each dose (for 8hrs

after initial application;

then, 2 hours after

morning doses, and

overnight for evening

doses).

Both treatments:

7 days

Both groups:

Aspiration of local

secretions by specialist

before 1st dose only.

No other antibiotic

treatments were

allowed throughout

the study period, but

appropriate drugs for

concomitant diseases

were permitted.

Systemic quinolone vs systemic + topical quinolone

De Miguel 1999 1) Systemic: oral 1) Systemic oral tablet 1) & 2) Systemic: All treatments: 7 days All groups: Aspiration Analgesics and

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ciprofloxacin

2) Systemic + topical:

oral ciprofloxacin +

topical ciprofloxacin

0.2%


+ topical eardrops

500mg twice daily (1

tablet every 12 hours)

2) Topical: 0.2%

ciprofloxacin, 3 drops 3

times daily (c0.15mL

every 8 hours)

before starting

treatment only.


during the study.

63.2% (79/125)

of all randomised

participants had

received previous


Esposito 1990 1) Systemic: oral

ciprofloxacin

2) Systemic + topical:



solution



+ topical eardrop

solution

1) & 2) Systemic:

250mg twice daily

2) Topical: 250

micrograms/mL, 3

drops twice daily

All treatment: 5-10

days (5 days initially;

if no cure after 5 days,

continued until cure

but not longer than 10

days total).

Not specified No participants

took any other drug

during the study. 63%

(38/60) had received

antibiotic treatment

for at least 5 days

before study treatment,

without significant

improvement.

Systemic + topical vs topical antibiotic alone

Systemic + topical non-quinolone vs topical quinolone

Supiyaphun 2000 1) Systemic + topical

non-quinolones: oral

amoxicillin + topical

chloramphenicol.

2) Systemic placebo

+ topical quinolone:

oral placebo + topical

ofloxacin

Systemic (both groups):

oral capsules

Topical (both groups):

eardrops/otic solution

1) Oral amoxicillin

500mg + topical 1%

chloramphenicol 3

drops; both 3 times

daily

2) Oral placebo 3 times

daily + topical 0.3%

ofloxacin 6 drops twice

daily

Both treatments:

2 weeks

Both groups:

Performed on Day 0

only.

No therapy with

systemic antibiotics or

any ototopical agents

within 2 weeks was

allowed.

Systemic + topical quinolone vs topical quinolone

De Miguel 1999 2) Systemic + topical:


topical ciprofloxacin

0.2% solution

3) Topical:


+ topical eardrop

solution

3) & 4) Topical eardrop

solution

2) Systemic: 500mg

twice daily (1 tablet

every 12 hours)

All groups: topical:

0.2% (groups 2 & 3)

All treatments: 7 days All groups: Aspiration

before starting

treatment only.

Analgesics and


during the study.

63.2% (79/125)

of all randomised

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ciprofloxacin 0.2%

4) Topical:

ciprofloxacin 0.5%

& 0.5% (group 4):

3 drops 3 times daily

(c0.15mL every 8

hours)

participants had

received previous


Esposito 1990 2) Systemic + topical:



solution

3) Topical:


solution


+ topical eardrop

solution

3) Topical eardrop

solution

2) Systemic: 250 mg

twice daily

2) & 3) Topical: 250

micrograms/mL, 3

drops twice daily

All treatments:

5-10 days (5 days

initially; if no cure after

5 days, continued until

cure but not longer

than 10 days total).

Not specified No participants took

any other drug during

the study.

63% (38/60) had

received antibiotic

treatment for at

least 5 days before

study treatment,

without significant

improvement.

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Table 05. Outcomes assessed

Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other

outcomes? Other notes

Participant or

ears?

Browning

1983

1) Participants

with active,

mucoid or

inactive ears

after 4 weeks

of treatment.

Participant

de Miguel

1999

1) Clinical

microbiologi-

cal cure - not

specified how

defined or

assessed.

Assessed at

days 1, 8 (end

of treatment)

and 15.

Unclear if

reported

results are for

day 8 or 15.

** 1) Hearing

assessment

- pure tone

audiometry.

Only reported

negative

findings in

relation to

ototoxicity

- see safety

column. **

1) Evidence

of ototoxicity

on hearing

assessment

(measured

by pure tone

audiometry)

- reported

negative

statement only.

2) Adverse

events

reported.

1) Bacteriology

assessed and

reported:

a) post-

treatment

bacteria

isolated for

treatment

failure cases.

b) pre- and

post-treatment

bacteria

in vitro

sensitivity.

Negative

bacterial

culture

appears to be

included in the

definition of

cure.

Participant?

Esposito 1990 1) Clinical

response:

participants

with cure

(dry ears),

improvement,

or failure.

Improvement

has been

grouped with

failure for this

review.

Stated response

24 hours and

1) All

participants

who were

clinically and

bacteriolog-

ically cured

24 hours after

5-10 days

treatment

confirmed

their clinical

status 14

days post-

treatment.

** 1) Hearing

assessment

- pure tone

audiometry

and vestibular

tests.

Measured

before and

24 hours post

treatment.

Only assessed

for groups

receiving

topical

1) Side effects:

’accurate

inquiry’ at

each clinical

control (every

2-3 days).

2) Ototoxicity:

audiometric

measurement

and vestibular

tests for

treatment

groups 2 and

3 (receiving

1)

Bacteriological

outcome:

1a)

Participants

with negative

aerobic

cultures

(reported

eradication,

persistence,

and super-

infection).

1b)

Participants

were

clinically and

bacteriology

assessed every

2-3 days;

evaluation

stated 24 hours

and 14 days

post 5-10 days

treatment.

Participant

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Table 05. Outcomes assessed (Continued )

Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

14 days after

5-10 days

treatment.

The results

reported

appear to be

for 24 hours

post-treatment

(i.e. day 6-11);

all those cured

confirmed

their status 2

weeks later.

ciprofloxacin.

Only reported

negative

findings in

relation to

ototoxicity

- see safety

column. **

topical

ciprofloxacin)

- before and

24 hours after

5-10 days

therapy.

Responsible

bacteria pre

and post

treatment.

1c)

Ciprofloxacin

resistance

(none

detected).

Bacteriology

assessed every

2-3 days;

evaluation

stated 24 hours

and 14 days

post treatment;

reported 24hr

results.

Esposito 1992 1) Clinical

response on

otoscopy:

participants

with cure

(dry ears),

improvement,

or failure.

Improvement

has been

grouped with

failure for this

review.

Stated response

12 hours,

14 days and

1) All

participants

who were

clinically and

bacteriolog-

ically cured

12 hours after

5-10 days

treatment,

confirmed

their clinical

status 14 and

21 days post

treatment; no

relapses were

observed.

** 1) Hearing

assessment -

audiometry

and vestibular

tests (all

participants).

Measured

before and

24 hours post

treatment.

Only reported

negative

findings in

relation to

ototoxicity

- see safety

1) Side effects:

“thorough

inquiry” at

each clinical

examination

(every 2-3

days).

2) Ototoxicity:

audiometric

measurement

and vestibular

tests for all

participants,

before and

24 hours post

treatment.

1)

Bacteriological

outcome:

1a)

Participants

with negative

aerobic

cultures

(reported

eradication or

persistence).

1b) Sensitivity

of 12hr post-

treatment

cultures to

ciprofloxacin

Participants

were

clinically and

bacteriology

assessed every

2-3 days;

evaluation

stated 12

hours, and 14

and 21 days

post 5-10 days

treatment.

Participant

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

21 days after

interrupting

5-10 days

treatment.

The results

reported

appear to be

for 12 hours

post-treatment

(i.e. after 5-

10 days); all

those cured

confirmed

their status 2

and 3 weeks

later.

column. ** and

gentamicin

(no resistance

detected).

Bacteriology

assessed every

2-3 days;

evaluation

stated 12 hours

and 14 and

21 days post

treatment;

reported 12hr

results.

Mira 1992 ** 1) Clinical

course of

disease:

recovered,

improved,

unchanged or

worsened.

Scale assessed

according to

absence or

degree of:

Fever,

symptoms

of infection,

negativisation

of culture.

Results were

not reported.

1) Safety: all

undesirable

events reported

by the

participant or

observed by

the physician

throughout the

study period.

1) Eradication

of isolated

bacteria -

reported

numbers

cultured by

pathogen

at baseline

(T0), end of

treatment (T7)

and 2 weeks

later (T21).

Participants

were assessed

at days 0

(baseline), 3

(for symptoms

and otoscopy

only), 7 (end

of treatment)

and 21.

Participant (+

overall scores

per group)

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

**

** 2) Symptom

severity scores

(3 point scale)

for otalgia,

otorrhoea

(quantity),

oedema, and

congestion.

Assessed and

reported scores

at days 0,

3, 7 (end of

treatment) and

21.

Presented

graphs of

overall scores

per group over

time with p-

values, but no

numerators

or standard

deviation. **

Papastavros

1989

Clinical

response:

Assessed

as cure,

recurrence,

improvement,

stagnation and

aggravation.

Reported cure,

improvement,

** 1) Systemic

adverse

effects and

appearance of

complications

or bothersome

allergic

reactions

(assessed

by close

1) Bacteriology

- assessed

before

treatment

(days -2 and

0), and every

10 days;

1a)

Bacteriological

response

Mucosal

appearance

and other

disease

related factors

included

in clinical

outcome

assessment.

Ears

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

or failure.

Assessed

according to

(criteria for

cure):

1) Discharge:

presence,

degree,

turbidity/

colour and

odour (absent)

2) Mucosal

appearance

(light pink)

3) Mucosal

oedema

granulations or

polyps (absent)

4) Reduction/

disappearance

or new

appearance

of associated

symptoms, not

attributable to

adverse effect

of treatment:

pain, otalgia,

tenderness

over mastoid,

local sensation

of pressure,

tinnitus,

headache,

imbalance,

monitoring by

independent

team of

internists) -

results were

not reported.

**

(aerobic and

anaerobic)

Classed as

eradication

(at least 2

consecutive

sterile cultures

at least 10 days

apart); relapse;

persistence;

new

infection; or

colonization.

Reported

eradication &

colonisation,

persistence or

recurrence.

Also reported

clinical

response

by initial

pathogen.

Unclear

whether

reported

results are for

after 10 days

or 2-3 weeks

treatment:

** 1b) Bacteria

sensitivities

(aerobic only)

- results not

reported. **

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

vertigo, fever,

stiff neck.

Antibiotic cure

rates varied

between 0%

(erythromycin

& piperacillin)

to 90%

(ciprofloxacin

+ metronida-

zole).

Reported

results for

atticoantral

and

tubotympanic

disease

separately.

Unclear

if results

reported

are for after

10 days or

2-3 weeks

treatment.

Povedano

1995

1) Clinical

success after

10 days

treatment:

cure,

improvement,

failure.

Improvement

has been

1)

Bacteriological

success:

negative

cultures or

persistent

bacteria.

Assessed

before and

Participant?

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

grouped with

failure, for this

review.

after 10 days

treatment.

Results seem

to also relate

to ears, but

N matches

participant

numbers (30

per group).

Supiyaphun

2000

1) Cure rate -

disappearance

of clinical

signs and

symptoms by

Day 14: otalgia

(assessed by

participant);

otorrhoea (i.e.

dry ear), and

middle ear

inflammation

(both

assessed on

microscopy by

investigator).

Dry ear has

been taken for

this outcome.

Results were

reported for

day 14.

1) Hearing

assessments:

Assessed and

reported pre-

and post-

treatment

audiometric

evaluation (i.e.

Days 0 and 14)

- assessed by

an authorised

audiologist for

ototoxicity

monitoring:

1a) Bone

conduction.

1b) Speech

reception

threshold

1c) ’Ototoxic

rate’:

percentage of

ears in which

the bone

conduction

1) Side effects

(recorded at

each visit).

2) Ototoxicity:

pre- and post-

treatment

audiometric

evaluation

assessed by

an authorised

audiologist:

2a) Bone

conduction.

2b) Speech

reception

threshold.

2c) ’Ototoxic

rate’:

percentage of

ears in which

the bone

conduction

or speech

reception

threshold were

1)

Improvement

in severity

scores of

clinical signs

and symptoms

by Day

14: otalgia

(assessed by

participant);

otorrhoea and

middle ear

inflammation

(both on

microscopy

by the

investigator).

2) Pre-

treatment bac-

teriology and

susceptibility

of isolates to

ofloxacin,

amoxicillin

and chloram-

Participants

were seen and

assessed on

Day 0, 7 and

14.

Results were

reported for

day 14.

Results were

reported as

percentage of

ears, not actual

numbers or

totals; but

rates reported

do not equate

to whole ears

when using

total numbers

of ears

(sometimes

match number

of participants

more closely).

% ears - but

rates do not

equate to

whole ears

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

and/or speech

reception

threshold were

elevated by

>5dB or a

high frequency

hearing loss

was detected

(with or

without

tinnitus).

elevated by

>5dB or a

high frequency

hearing loss

was detected

(with or

without

tinnitus).

phenicol.

3) Drug

compliance

- scored

according to

number of

forgotten doses

within the

previous seven

days - good

compliance (0-

3 missed doses)

was noted

by >90% of

participants in

both groups.

Yuen 1994 1) Participants

with

completely dry

ear - reported

numbers at

week 2.

** 1) Size of

perforation

(<25%, 25

-75%, or

>75%).

Reported

baseline results

only **

** 1) Hearing

level -

pure tone

audiogram.

Only reported

summary

statement,

for absence

of significant

change in bone

conduction

thresholds at

frequencies

0.5-4kHz. **

1) Sign

of allergic

reaction

documented

by the authors.

** 1) Degree of

severity (mild,

moderate,

or severe) of

symptoms

of otalgia,

tinnitus,

hearing loss,

dizziness

and aural

discharge.

Documented

on card daily

by participant

- results not

reported **

** 2) Middle

ear mucosal

All outcomes

assessed before

treatment and

weekly for 2

weeks (end of

treatment, and

1 week later).

Participant

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Study ID

CSOM

Resolution Healing

Time to

resolution

Time to

reappearance

Hearing

improvement Safety

Other


Participant or

ears?

inflammation

(mild,

moderate, or

severe).

Documented

by authors

at each visit;

reported

baseline results

only **

** 3) Nature

of discharge

(watery,

mucoid, or

purulent).

Documented

by authors

at each visit;

reported

baseline results

only **

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Table 06. Safety

Study ID Treatment comparison Allergic reaction Ototoxicity AE caused withdrawal Other AE

de Miguel 1999 1) Systemic quinolone: oral

500mg ciprofloxacin.


quinolone: oral 500mg +

topical 0.2% ciprofloxacin.

3) Topical quinolone: 0.2%

ciprofloxacin.

4) Topical quinolone: 0.5%

ciprofloxacin.

(N = 25 per group)

There was no evidence

of ’cochleovestibular’

dysfunction during or after

treatment for any of the

treatment arms.

There were no cases of

ototoxicity on audiometry

carried out after treatment.

Other adverse events:

1) Oral ciprofloxacin: 8

gastralgia

2) Oral + topical cipro 0.2%:

5 gastralgia; 1 otomycosis

3) Topical cipro 0.2%: 2

otomycosis

4) Topical cipro 0.5%: 4

otomycosis

Esposito 1990 1) Systemic quinolone: oral

ciprofloxacin, 250mg.


quinolone: oral ciprofloxacin

250mg + ciprofloxacin

eardrops 250mg/mL.

3) Topical quinolone

eardrops: ciprofloxacin

250mg/mL.

(N = 20 per group)

No worsening of audiometric

and vestibular function

related to local therapy was

observed (only assessed in

participants who received

topical ciprofloxacin).

No side effected was

recorded in any participant.

Esposito 1992 1) Systemic non-quinolone:

intramuscular gentamicin

sulphate, 80mg.


ciprofloxacin hydrochloride

eardrops, 250

microgram/ml.

(N = 30 per group)

No worsening of the

audiometric function after

local or parenteral therapy

was observed.

No side effect was recorded

for any participant.

Mira 1992 1) Systemic non-quinolone:

intramuscular ceftizoxime +

topical saline solution (N =

120).

2) Systemic + topical non-

quinolone: intramuscular +

topical ceftizoxime (N=127).

“All undesirable effects

resulted from the systemic

treatment”:

1) Systemic ceftizoxime

only:

Any event: 2 participants

(1.67%):

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Table 06. Safety (Continued )

Study ID Treatment comparison Allergic reaction Ototoxicity AE caused withdrawal Other AE

1 skin rash, 1 epigastric pain

2) Systemic+topical

ceftizoxime:

Any event: 1 participant

(0.79%):

1 diarrhoea

Supiyaphun 2000 1) Systemic + topical

non-quinolones: oral

amoxicillin 500mg + topical

chloramphenicol 0.1% (N=

40 participants, 45 ears).

2) Topical quinolone: oral

placebo + topical ofloxacin

0.3% (N=39 participants,

44 ears).

A considerable deterioration

was observed in bone

conduction (P =

0.007) in amoxicillin +

chloramphenicol treated

ears.

Meanwhile, ofloxacin treated

ears improved instead.

The ototoxic rate (percentage

of ears in which the elevation

of bone conduction or

speech reception threshold

was greater than 5dB or had

a high frequency hearing

loss, with or without

tinnitus) was significantly

higher in amoxicillin+

chloramphenicol treated ears

than in ofloxacin treated ears

(p <0.001 for BC and p=

0.03 for SRT)

1) Systemic+topical non-

quinolones:

1 tinnitus (disappeared after

discontinuing eardrops);

37% treated ears had mild

to moderate soreness from

eardrops;

2 fungal superimposition

(both resolved after specific

treatment).


2 cases of soreness from

eardrops (5.1%);

1 fungal superimposition

(resolved after specific

treatment).

Yuen 1994 1) Systemic non-quinolone:

oral Augmentin 375mg.


ofloxacin 0.3% eardrops.

There was no

hypersensitivity reaction to

the topical ofloxacin.

There were no significant

differences between the

pre-treatment and post-

treatment pure-tone

audiograms of bone

conduction thresholds at

frequencies of 0.5, 1, 2 and

4 kHz.

1) Oral Augmentin:

1 participant did not

complete the course because

of gastric upset - this

participant was excluded

from the analysis.

1) Oral Augmentin:

1 participant did not

complete the course because

of gastric upset - this

participant was excluded

from the analysis.

2) Topical ofloxacin:

no participants complained

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Tab

le06.

Safe

ty(C

onti

nue

d)

Stu

dy

IDT

reat

men

tco

mp

aris

on

All

ergi

cre

acti

on

Oto

toxi

city

AE

cau

sed

wit

hd

raw

alO

ther

AE

ofad

vers

esi

de

effe

cts.



Table 07. Supiyaphun 2000 hearing analysis: pre- and post-treatment audiometry (2 weeks)

Assessment

Ofloxacin pre

trtmt

Ofloxacin post

trtmt

Ofloxacin p-

value

Amox+CRP pre

trtmt

Amox+CRP

post-trtmt

Amox+CRP p-

value

Bone

conduction

(BC) (dB +/-

SD)

P-value from

paired t test

23.4 +/-9.7 21.2 +/-8.5 p<0.001 22.8 +/-10.4 24.8 +/-10.4 p=0.007

Speech reception

threshold (SRT)

(dB +/- SD)

P-value from chi

squared test.

44.6 +/-15.8 41.2 +/-16.6 p=0.002 40.6 +/-18.1 40.9 +/-11.7 p=0.81

Table 08. Supiyaphun 2000 hearing analysis: Ototoxic rate

Assessment Ofloxacin Amox+CRP chi-square p-value

Bone conduction (BC) ototoxic rate (%) 5.3% 45% p<0.001

Speech reception threshold (SRT) ototoxic rate (%) 10.5% 30% p=0.033

A N A L Y S E S

Comparison 01. Systemic antibiotic vs topical antiseptic

Outcome titleNo. of

studies

No. of

participants Statistical method Effect size

01 Treatment failure (persistent

discharge) at 2-4 weeks

2 152 Relative Risk (Fixed) 95% CI 0.81 [0.61, 1.08]

Comparison 02. Systemic antibiotic versus topical antibiotic

Outcome titleNo. of

studies

No. of


01 Treatement failure (persistent

discharge)

Relative Risk (Fixed) 95% CI Subtotals only

Comparison 03. Systemic antibiotic vs systemic + topical antibiotic

Outcome titleNo. of

studies

No. of


01 Systemic quinolone vs systemic

+ topical quinolone

2 90 Relative Risk (Fixed) 95% CI 2.75 [1.38, 5.46]



Comparison 04. Systemic + topical antibiotic vs topical antibiotic

Outcome titleNo. of

studies

No. of


01 Systemic+topical non-

quinolone vs topical quinolone


02 Treatment failure (persistent

discharge)


I N D E X T E R M S

Medical Subject Headings (MeSH)

Administration, Oral; Administration, Topical; Anti-Bacterial Agents [∗administration & dosage]; Chronic Disease; Otitis Media,

Suppurative [∗drug therapy]; Randomized Controlled Trials; Tympanic Membrane Perforation [∗complications]

MeSH check words

Humans

C O V E R S H E E T

Title Systemic antibiotics versus topical treatments for chronically discharging ears with under-

lying eardrum perforations

Authors Macfadyen CA, Acuin JM, Gamble C

Contribution of author(s) Jose Acuin (JA) was the primary author for the Cochrane Review ’Interventions for chronic

suppurative otitis media’ (Acuin 1998), that this review replaces.

Carolyn Macfadyen (CM) designed the current review, in consultation with JA.

CM and JA worked with Gemma Healy (GH) and Carolyn Doree (CD), the Cochrane

ENT Group Trials Search Co-ordinators, for the search strategy development. GH ran the

initial electronic searches, and performed a preliminary screen of the search results; CD ran

the search update in March 2005. Both searches were carried out independently.

CM and JA independently reviewed the titles and abstracts identified during the search for

preliminary assessment, and CM retrieved and reviewed the full papers for all potentially

relevant studies. CM will organise retrieval of future unpublished studies, and will contact

authors for additional information or clarifications where needed.

CM assessed the methodological quality of all trials identified for inclusion, extracted data,

and entered data into Review Manager 4.2 for analysis. JA and Carrol Gamble (CG) provided

a second opinion on trials CM had selected for inclusion; CG reviewed those where there was

any ambiguity about the methods used, for the methodological quality and data extraction;

and JA provided further information where this had been obtained from authors of trials

included in the previous review ’Interventions for chronic suppurative otitis media’ (Acuin

1998). The three authors resolved any disagreements through discussion.

None of the authors have worked on any trials included in the review.

CM wrote the final review, with statistical and clinical input from CG and JA. All three

authors provided the methodological perspective; CG also provides the statistical perspective

and JA the clinical perspective.

Issue protocol first published /

Review first published 2006/1

Date of most recent amendment 16 November 2005



Date of most recent

SUBSTANTIVE amendment

15 November 2005

What’s New Information not supplied by author

Date new studies sought but

none found

Information not supplied by author

Date new studies found but not

yet included/excluded


Date new studies found and

included/excluded


Date authors’ conclusions

section amended


Contact address Ms Carolyn Macfadyen

Research Associate

International Health Research Group

Liverpool School of Tropical Medicine

Pembroke Place

Liverpool

L3 5QA

UK

E-mail: [email protected] ; [email protected]

Tel: +44 0 7946 620371

Fax: +44 151 705 3364

DOI 10.1002/14651858.CD005608

Cochrane Library number CD005608

Editorial group Cochrane Ear, Nose and Throat Disorders Group

Editorial group code HM-ENT

G R A P H S A N D O T H E R T A B L E S

Analysis 01.01. Comparison 01 Systemic antibiotic vs topical antiseptic, Outcome 01 Treatment failure

(persistent discharge) at 2-4 weeks

Review: Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations

Comparison: 01 Systemic antibiotic vs topical antiseptic

Outcome: 01 Treatment failure (persistent discharge) at 2-4 weeks

Study Systemic antibiotic Topical antiseptic Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Browning 1983 8/13 13/20 22.8 0.95 [ 0.55, 1.62 ]

Papastavros 1989 33/71 29/48 77.2 0.77 [ 0.55, 1.08 ]

Total (95% CI) 84 68 100.0 0.81 [ 0.61, 1.08 ]

Total events: 41 (Systemic antibiotic), 42 (Topical antiseptic)

Test for heterogeneity chi-square=0.41 df=1 p=0.52 I² =0.0%

Test for overall effect z=1.44 p=0.1

0.1 0.2 0.5 1 2 5 10

Systemic Ab better Antiseptic better



Analysis 02.01. Comparison 02 Systemic antibiotic versus topical antibiotic, Outcome 01 Treatement failure

(persistent discharge)


Comparison: 02 Systemic antibiotic versus topical antibiotic

Outcome: 01 Treatement failure (persistent discharge)

Study Systemic antibiotic Topical antibiotic Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Systemic non-quinolone vs topical non-quinolone: discharge at 4 weeks

Browning 1983 8/13 15/18 100.0 0.74 [ 0.46, 1.19 ]

Subtotal (95% CI) 13 18 100.0 0.74 [ 0.46, 1.19 ]

Total events: 8 (Systemic antibiotic), 15 (Topical antibiotic)

Test for heterogeneity: not applicable


02 Systemic non-quinolone vs topical quinolone: discharge at 1-2 weeks

Esposito 1992 17/30 5/30 42.6 3.40 [ 1.44, 8.03 ]

Yuen 1994 20/27 7/29 57.4 3.07 [ 1.55, 6.07 ]

Subtotal (95% CI) 57 59 100.0 3.21 [ 1.88, 5.49 ]




03 Systemic quinolone vs topical quinolone: discharge at 1-2 weeks

Esposito 1990 12/20 3/20 23.7 4.00 [ 1.33, 12.05 ]

Povedano 1995 15/30 5/30 39.5 3.00 [ 1.25, 7.21 ]

de Miguel 1999 10/25 7/50 36.8 2.86 [ 1.24, 6.61 ]

Subtotal (95% CI) 75 100 100.0 3.18 [ 1.87, 5.43 ]




0.01 0.1 1 10 100

Systemic Ab better Topical Ab better



Analysis 03.01. Comparison 03 Systemic antibiotic vs systemic + topical antibiotic, Outcome 01 Systemic

quinolone vs systemic + topical quinolone


Comparison: 03 Systemic antibiotic vs systemic + topical antibiotic

Outcome: 01 Systemic quinolone vs systemic + topical quinolone

Study Systemic quinolone Systemc+topical quin Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Treatment failure (persistent discharge) at 1-2 weeks

Esposito 1990 12/20 5/20 62.5 2.40 [ 1.04, 5.55 ]

de Miguel 1999 10/25 3/25 37.5 3.33 [ 1.04, 10.69 ]

Total (95% CI) 45 45 100.0 2.75 [ 1.38, 5.46 ]

Total events: 22 (Systemic quinolone), 8 (Systemc+topical quin)



0.01 0.1 1 10 100

Systemc alone better Systemic+top better

Analysis 04.01. Comparison 04 Systemic + topical antibiotic vs topical antibiotic, Outcome 01 Systemic+

topical non-quinolone vs topical quinolone


Comparison: 04 Systemic + topical antibiotic vs topical antibiotic

Outcome: 01 Systemic+topical non-quinolone vs topical quinolone

Study Systemc+top non-quin Topical quinolone Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Treatment failure (persistent discharge) at 2 weeks

Supiyaphun 2000 28/45 10/44 100.0 2.74 [ 1.52, 4.94 ]

Subtotal (95% CI) 45 44 100.0 2.74 [ 1.52, 4.94 ]

Total events: 28 (Systemc+top non-quin), 10 (Topical quinolone)



02 Ototoxic rate (bone conduction)

Supiyaphun 2000 20/45 2/44 100.0 9.78 [ 2.43, 39.37 ]

Subtotal (95% CI) 45 44 100.0 9.78 [ 2.43, 39.37 ]




03 Ototoxic rate (Speech Reception Threshold)

Supiyaphun 2000 13/45 5/44 100.0 2.54 [ 0.99, 6.53 ]

Subtotal (95% CI) 45 44 100.0 2.54 [ 0.99, 6.53 ]

0.01 0.1 1 10 100

Systemic+top better Topical quin better (Continued . . . )



(. . . Continued)

Study Systemc+top non-quin Topical quinolone Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI




0.01 0.1 1 10 100

Systemic+top better Topical quin better

Analysis 04.02. Comparison 04 Systemic + topical antibiotic vs topical antibiotic, Outcome 02 Treatment

failure (persistent discharge)


Comparison: 04 Systemic + topical antibiotic vs topical antibiotic

Outcome: 02 Treatment failure (persistent discharge)

Study Systemic+topical Ab Topical antibiotic Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Systemic+topical quinolone vs topical quinolone: discharge at 1-2 weeks

Esposito 1990 5/20 3/20 39.1 1.67 [ 0.46, 6.06 ]

de Miguel 1999 3/25 7/50 60.9 0.86 [ 0.24, 3.04 ]

Subtotal (95% CI) 45 70 100.0 1.17 [ 0.48, 2.86 ]

Total events: 8 (Systemic+topical Ab), 10 (Topical antibiotic)



02 Systemic+topical non-quinolone vs topical quinolone: discharge at 2 weeks

Supiyaphun 2000 28/45 10/44 100.0 2.74 [ 1.52, 4.94 ]

Subtotal (95% CI) 45 44 100.0 2.74 [ 1.52, 4.94 ]

Total events: 28 (Systemic+topical Ab), 10 (Topical antibiotic)



0.1 0.2 0.5 1 2 5 10

Systemic+top better Topical alone better



systemic antibiotics versus topical treatments for ...complications, healingtheeardrum, andimproving...

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