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
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)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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).
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
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
2Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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,
3Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
4Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
#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.
5Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
6Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
7Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
• 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).
8Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
9Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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.
Treatment failure (Figure: comparison 02, outcome 01, subgroup 02)
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
10Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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.
Treatment failure (Figure: comparison 02, outcome 01, subgroup 03)
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.
No longer-term data were reported, although Esposito 1990 re-
ported that all participants who were clinically and bacteriologi-
cally cured 24 hours after five to ten days treatment, confirmed
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.
Improvement in hearing threshold
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
Data relating to adverse events have been summarised in additional
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
Data relating to adverse events have been summarised in additional
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
Esposito 1990 appear to be for 24 hours after five to ten 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 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.
Improvement in hearing threshold
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
11Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Data relating to adverse events have been summarised in additional
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.
Improvement in hearing threshold
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.
Treatment failure (Figure: comparison 04, outcome 02, subgroup 01)
No trials reported results after two weeks: the results reported for
Esposito 1990 appear to be for 24 hours after five to ten 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 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.
No longer-term data were reported, although Esposito 1990 re-
ported that all participants who were clinically and bacteriologi-
cally cured 24 hours after five to ten days treatment, confirmed
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.
Improvement in hearing threshold
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
Data relating to adverse events have been summarised in additional
Table 06.
12Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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.
13Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
14Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
15Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
R E F E R E N C E S
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∗Indicates the major publication for the study
23Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
Methods Randomised controlled trial
Participants See Table 03
60 adults, aged 18 or older, with CSOM in the acute stage were included (20 per group).
Interventions See Table 04
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.
24Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Outcomes See Table 05
Review outcomes assessed:
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.
Allocation concealment B – Unclear
Study Esposito 1992
Methods Randomised controlled trial
Participants See Table 03
60 adults aged 18-65 years, with CSOM in the acute stage, with perforation of the tympanic membrane,
were included (30 per group).
Interventions See Table 04
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.
Outcomes See Table 05
Review outcomes assessed:
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).
** 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 powder was provided by Bayer Italia Spa, Milan, Italy;
gentamicin injectable vials were provided by Schering Plough, Milan, Italy.
Allocation concealment B – Unclear
25Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Study Mira 1992
Methods Randomised controlled trial
Participants See Table 03
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).
Interventions See Table 04
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.
Outcomes See Table 05
Review outcomes assessed:
** 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
* Outcomes not included in this review were also assessed - see table 05 *
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.
Allocation concealment B – Unclear
Study Papastavros 1989
Methods Randomised controlled trial
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.
Interventions See Table 04
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.
26Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
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.
Outcomes See Table 05
Review outcomes assessed:
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)**
* Outcomes not included in this review were also assessed - see table 05 *
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
Methods Randomised controlled trial
Participants See Table 03
60 adults (aged 18-65), with chronic otorrhoea in the active phase, were randomised and analysed (30 per
treatment group).
Interventions See Table 04
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.
Outcomes See Table 05
Review outcomes assessed:
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.
* Outcomes not included in this review were also assessed - see table 05 *
Notes Setting: Appears to be hospital based
Location: Spain (Cordoba)?
Allocation concealment B – Unclear
Study Supiyaphun 2000
Methods Randomised controlled trial
Participants See Table 03
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).
Interventions See Table 04
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
27Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Duration (both groups): 2 weeks
Aural toilet (both groups): performed on Day 0 only.
Outcomes See Table 05
Review outcomes assessed:
1) CSOM resolution/failure (persistent discharge at 2 to 4 weeks)
2) Improvement in hearing threshold
3) Adverse events (including assessment of ototoxicity)
* Outcomes not included in this review were also assessed - see table 05 *
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.
Allocation concealment B – Unclear
Study Yuen 1994
Methods Randomised controlled trial
Participants See Table 03
60 adults (aged 18-70) with active CSOM with central perforation recruited; 56 analysed.
Interventions See Table 04
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.
Outcomes See Table 05
Review outcomes assessed:
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
* Outcomes not included in this review were also assessed - see table 05 *
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
28Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Study de Miguel 1999
Methods Randomised controlled trial
Participants See Table 03
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).
Interventions See Table 04
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).
Outcomes See Table 05
Review outcomes assessed:
1) CSOM resolution/failure (persistent discharge)
Unclear whether the outcome reported is for day 8 or 15.
** 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 (hospital/clinic?).
Location: Gran Canaria.
Study time period: Conducted over a 2-year period.
Article in Spanish.
Trial in other CSOM reviews: steroids.
Allocation concealment B – Unclear
* 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
29Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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.
30Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERVENTION
No participants were allocated topical treatment (systemic antibiotics only).
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
31Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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).
Gyde 1981 (INTERVENTION)
For topical antibiotics review (comparisons between topical non-quinolone antibiotics; no systemic treatment
group).
Gyde 1982 (INTERVENTION)
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
No participants were allocated topical treatment (systemic antibiotics only).
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).
Howie 1974 PARTICIPANTS
Participants had acute otitis media with the presence of middle ear fluid.
INTERVENTION
No participants were allocated topical treatments (oral only).
Howie 1985 PARTICIPANTS
Participants had acute or recurrent acute otitis media.
INTERVENTION
No participants were allocated topical treatment (systemic antibiotics only).
32Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
No participants were allocated topical treatments (oral antibiotics only).
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
No participants were allocated topical treatments (oral antibiotics only).
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
33Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
No participants were allocated topical treatments (oral antibiotics only).
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
34Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
chronic suppurative otitis media.
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
No participants were allocated topical treatments (oral antibiotics only).
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).
35Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
chronic suppurative otitis media.
INTERVENTION
No participants were allocated topical treatments (oral antibiotics only).
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
Not a randomised controlled trial.
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
Not a randomised controlled trial.
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)
36Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of excluded studies (Continued )
For topical antibiotics review (topical quinolone antibiotic versus non-quinolone antibiotic versus antiseptic;
all topical - no systemic treatment groups).
van Hasselt 1998 (INTERVENTION)
For topical antibiotics review (topical quinolone antibiotic versus topical non-quinolone antibiotic, using 2
treatment regimens for each; no systemic treatment groups).
van Hasselt 2002 (INTERVENTION)
For topical antibiotics review (topical quinolone versus topical antiseptic versus placebo; no systemic treatment
groups).
37Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
Treatment allocation
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).
38
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
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&S
on
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td
Table 01. Methodological quality of included studies (Continued )
Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up
(and results not reported
separately in trial report).
The distribution of the 4
diagnostic groups was not
reported.
Esposito 1990 Unclear
Treatment allocation
described as random, but
randomisation method was
not stated.
Unclear
Allocation concealment not
reported - nor was blinding.
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
Blinding not mentioned.
Adequate
No withdrawal was reported.
60 participants were
reported as entered into the
trial and were analysed (20
per group).
Esposito 1992 Unclear
Treatment allocation
described as random, but
randomisation method was
not stated.
Unclear
Allocation concealment not
reported - nor was blinding.
Yes
Balanced for age and sex.
No other baseline characters
were reported.
Unclear
Blinding not mentioned.
Adequate
No withdrawal was reported.
60 participants were
reported as entered into the
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
Allocation concealment
not reported - but trial was
reported to be single blind.
Yes
Groups comparable at
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
numbers were included in
the analyses.39
Syste
mic
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tics
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atm
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disc
harg
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ears
with
un
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eard
rum
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ns
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Table 01. Methodological quality of included studies (Continued )
Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up
Papastavros 1989 Inadequate
Treatment allocation
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
Allocation concealment not
reported - nor was blinding.
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
Blinding not mentioned.
Adequate
No withdrawal was reported.
90 participants with 119
ears (71 antibiotics, 48
antiseptics) were reported as
entered into the trial and
were analysed.
Povedano 1995 Unclear
Treatment allocation
described as random, but
randomisation method was
not stated.
Unclear
Allocation concealment not
reported - nor was blinding.
Yes
Groups comparable at
baseline for age, sex and
bacteriology.
Unclear
Blinding not mentioned.
Adequate
All participants were
reported to have completed
the study, with no dropouts.
Supiyaphun 2000 Unclear
Treatment allocation
described as random, but
randomisation method was
not stated.
Unclear
Allocation concealment
not mentioned - but
’investigator-blinded’ trial.
Yes
Groups comparable at
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
40
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mic
an
tibio
tics
versu
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atm
en
tsfo
rch
ron
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disc
harg
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ears
with
un
derly
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eard
rum
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ratio
ns
(Revie
w)
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pyrig
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Table 01. Methodological quality of included studies (Continued )
Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up
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
Groups comparable at
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
Blinding not mentioned.
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.
41
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tics
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tsfo
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ron
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with
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eard
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ns
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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)
Not reported Not reported Unclear - reported
at participant level.
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:
Not reported Not reported Unclear - reported
at participant level,
but reported scores
without numbers.
Participants
42Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Table 02. Bilateral Disease: Numbers for Ears vs Participants (Continued )
Study ID # of particpants # of ears % bilateral cases
Handling bilat
cases Results: pt or ears?
(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:
(40 oral amoxicillin
+ topical
chloramphenicol;
39 topical ofloxacin
drops)
89 analysed ears:
(45 oral amoxicillin
+ 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.
43Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Table 02. Bilateral Disease: Numbers for Ears vs Participants (Continued )
Study ID # of particpants # of ears % bilateral cases
Handling bilat
cases Results: pt or ears?
Yuen 1994 60 recruited
participants:
(30 oral Augmentin;
30 topical
ofloxacin).
56 analysed
participants:
(27 oral Augmentin;
29 topical
ofloxacin).
Not reported Not reported Unclear - reported
at participant level.
Participants
44Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
45
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altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
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by
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&S
on
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td
Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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
46
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mic
an
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tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
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&S
on
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td
Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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
47
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tics
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atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
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&S
on
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td
Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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
48
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with
un
derly
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eard
rum
perfo
ratio
ns
(Revie
w)
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©2006
Th
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och
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olla
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n.P
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on
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Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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.
49
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tics
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atm
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tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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pyrig
ht
©2006
Th
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och
ran
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olla
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ratio
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Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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
50
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atm
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tsfo
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ically
disc
harg
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ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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pyrig
ht
©2006
Th
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och
ran
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olla
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ratio
n.P
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Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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
51
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an
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tics
versu
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atm
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tsfo
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ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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pyrig
ht
©2006
Th
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och
ran
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olla
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ratio
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Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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
52
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disc
harg
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ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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ht
©2006
Th
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och
ran
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olla
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ratio
n.P
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td
Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )
Study ID
CSOM
diagnosis
Otitis
exclusions
Other elig
criteria
Disease
duration Bacteriology?
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.
53
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an
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tics
versu
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altre
atm
en
tsfo
rch
ron
ically
disc
harg
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ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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ht
©2006
Th
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och
ran
eC
olla
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td
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
depended on sensitivity
of bacteria isolated at
baseline.
1) Systemic antibiotics:
oral (formulation not
specified).
3) Topical antiseptics:
insufflation of
antiseptic powder.
1) Systemic antibiotics:
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
1) Systemic antibiotics:
a) intravenous;
b-d) oral
2) Topical antiseptics:
a) Hydrogen peroxide:
instillation of drops
b) Borax: insufflation
of powder.
1) Systemic antibiotics:
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)
1) Systemic antibiotics:
21.4 days
(19.4 tubotympanic;
24.3 atticoantral)
2) Topical antiseptics:
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
54
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atm
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tsfo
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disc
harg
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ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
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ht
©2006
Th
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Table 04. Intervention regimens used (Continued )
Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds
+ 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).
55
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an
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tics
versu
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pic
altre
atm
en
tsfo
rch
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ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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©2006
Th
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n.P
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td
Table 04. Intervention regimens used (Continued )
Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds
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
depended on sensitivity
of bacteria isolated at
baseline.
1) Systemic antibiotics:
oral (formulation not
specified)
2) Topical antibiotics:
eardrops
1) Systemic antibiotics:
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
56
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mic
an
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tics
versu
sto
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altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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ht
©2006
Th
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ran
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ratio
n.P
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by
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&S
on
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td
Table 04. Intervention regimens used (Continued )
Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds
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)
2) Topical quinolone:
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
1) Systemic oral tablet
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
improvement.57
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 04. Intervention regimens used (Continued )
Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds
Povedano 1995 1) Systemic: oral
ciprofloxacin
2) Topical:
ciprofloxacin in saline
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
58
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mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 04. Intervention regimens used (Continued )
Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds
ciprofloxacin
2) Systemic + topical:
oral ciprofloxacin +
topical ciprofloxacin
0.2%
2) Systemic oral tablet
+ 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.
antipyretics allowed
during the study.
63.2% (79/125)
of all randomised
participants had
received previous
antibiotic treatment.
Esposito 1990 1) Systemic: oral
ciprofloxacin
2) Systemic + topical:
oral ciprofloxacin +
ciprofloxacin in saline
solution
1) Systemic oral tablet
2) Systemic oral tablet
+ 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:
oral ciprofloxacin +
topical ciprofloxacin
0.2% solution
3) Topical:
2) Systemic oral tablet
+ 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
antipyretics allowed
during the study.
63.2% (79/125)
of all randomised
59
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 04. Intervention regimens used (Continued )
Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds
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
antibiotic treatment.
Esposito 1990 2) Systemic + topical:
oral ciprofloxacin +
ciprofloxacin in saline
solution
3) Topical:
ciprofloxacin in saline
solution
2) Systemic oral tablet
+ 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.
60
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
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
61
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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
62
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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)
63
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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
64
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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. **
65
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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?
66
Syste
mic
an
tibio
tics
versu
sto
pic
altre
atm
en
tsfo
rch
ron
ically
disc
harg
ing
ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
Co
pyrig
ht
©2006
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td
Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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
67
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with
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derly
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eard
rum
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ns
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Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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
68
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ns
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Table 05. Outcomes assessed (Continued )
Study ID
CSOM
Resolution Healing
Time to
resolution
Time to
reappearance
Hearing
improvement Safety
Other
outcomes? Other notes
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 **
69
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ears
with
un
derly
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eard
rum
perfo
ratio
ns
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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.
2) Systemic + topical
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.
2) Systemic + topical
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.
2) Topical quinolone:
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%):
70
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derly
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eard
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ns
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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) Topical quinolone:
2 cases of soreness from
eardrops (5.1%);
1 fungal superimposition
(resolved after specific
treatment).
Yuen 1994 1) Systemic non-quinolone:
oral Augmentin 375mg.
2) Topical quinolone:
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
71
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tics
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disc
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ears
with
un
derly
ing
eard
rum
perfo
ratio
ns
(Revie
w)
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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.
72Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
participants Statistical method Effect size
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
participants Statistical method Effect size
01 Systemic quinolone vs systemic
+ topical quinolone
2 90 Relative Risk (Fixed) 95% CI 2.75 [1.38, 5.46]
73Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Comparison 04. Systemic + topical antibiotic vs topical antibiotic
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Systemic+topical non-
quinolone vs topical quinolone
Relative Risk (Fixed) 95% CI Subtotals only
02 Treatment failure (persistent
discharge)
Relative Risk (Fixed) 95% CI Subtotals only
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
74Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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
Information not supplied by author
Date new studies found and
included/excluded
Information not supplied by author
Date authors’ conclusions
section amended
Information not supplied by author
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
75Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.01. Comparison 02 Systemic antibiotic versus topical antibiotic, Outcome 01 Treatement failure
(persistent discharge)
Review: Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations
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
Test for overall effect z=1.25 p=0.2
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 ]
Total events: 37 (Systemic antibiotic), 12 (Topical antibiotic)
Test for heterogeneity chi-square=0.03 df=1 p=0.85 I² =0.0%
Test for overall effect z=4.25 p=0.00002
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 ]
Total events: 37 (Systemic antibiotic), 15 (Topical antibiotic)
Test for heterogeneity chi-square=0.25 df=2 p=0.88 I² =0.0%
Test for overall effect z=4.26 p=0.00002
0.01 0.1 1 10 100
Systemic Ab better Topical Ab better
76Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 03.01. Comparison 03 Systemic antibiotic vs systemic + topical antibiotic, Outcome 01 Systemic
quinolone vs systemic + topical quinolone
Review: Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations
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)
Test for heterogeneity chi-square=0.21 df=1 p=0.65 I² =0.0%
Test for overall effect z=2.89 p=0.004
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
Review: Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations
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)
Test for heterogeneity: not applicable
Test for overall effect z=3.34 p=0.0008
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 ]
Total events: 20 (Systemc+top non-quin), 2 (Topical quinolone)
Test for heterogeneity: not applicable
Test for overall effect z=3.21 p=0.001
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 . . . )
77Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
(. . . Continued)
Study Systemc+top non-quin Topical quinolone Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Total events: 13 (Systemc+top non-quin), 5 (Topical quinolone)
Test for heterogeneity: not applicable
Test for overall effect z=1.94 p=0.05
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)
Review: Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations
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)
Test for heterogeneity chi-square=0.52 df=1 p=0.47 I² =0.0%
Test for overall effect z=0.35 p=0.7
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)
Test for heterogeneity: not applicable
Test for overall effect z=3.34 p=0.0008
0.1 0.2 0.5 1 2 5 10
Systemic+top better Topical alone better
78Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd