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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 1 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd TABLE OF CONTENTS ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 2 OBJECTIVES ...... 4 CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW ...... 4 SEARCH METHODS FOR IDENTIFICATION OF STUDIES ...... 4 METHODSOFTHEREVIEW ...... 5 DESCRIPTIONOFSTUDIES ...... 7 METHODOLOGICALQUALITY ...... 9 RESULTS...... 9 DISCUSSION ...... 13 AUTHORS’CONCLUSIONS ...... 14 NOTES...... 14 POTENTIALCONFLICTOFINTEREST ...... 16 ACKNOWLEDGEMENTS ...... 16 SOURCESOFSUPPORT ...... 16 REFERENCES ...... 16 TABLES ...... 24 Characteristics of included studies ...... 24 Characteristics of excluded studies ...... 29 ADDITIONALTABLES...... 38 Table 01. Methodological quality of included studies ...... 38 Table 02. Bilateral Disease: Numbers for Ears vs Participants...... 42 Table 03. Participant eligibility criteria, including CSOM diagnostic criteria ...... 45 Table 04. Intervention regimens used ...... 54 Table05.Outcomesassessed...... 61 Table06.Safety ...... 70 Table 07. Supiyaphun 2000 hearing analysis: pre- and post-treatment audiometry (2 weeks) ...... 73 Table 08. Supiyaphun 2000 hearing analysis: Ototoxic rate ...... 73 ANALYSES ...... 73 Comparison 01. Systemic antibiotic vs topical antiseptic ...... 73 Comparison 02. Systemic antibiotic versus topical antibiotic...... 73 Comparison 03. Systemic antibiotic vs systemic + topical antibiotic ...... 73 Comparison 04. Systemic + topical antibiotic vs topical antibiotic ...... 74 INDEXTERMS ...... 74 COVERSHEET ...... 74 GRAPHSANDOTHERTABLES ...... 75 Analysis 01.01. Comparison 01 Systemic antibiotic vs topical antiseptic, Outcome 01 Treatment failure (persistent 75 discharge)at2-4weeks ...... Analysis 02.01. Comparison 02 Systemic antibiotic versus topical antibiotic, Outcome 01 Treatement failure (persistent 76 discharge) ...... Analysis 03.01. Comparison 03 Systemic antibiotic vs systemic + topical antibiotic, Outcome 01 Systemic quinolone vs 77 systemic + topical quinolone ...... Analysis 04.01. Comparison 04 Systemic + topical antibiotic vs topical antibiotic, Outcome 01 Systemic+topical non- 77 quinolone vs topical quinolone ...... Analysis 04.02. Comparison 04 Systemic + topical antibiotic vs topical antibiotic, Outcome 02 Treatment failure 78 (persistentdischarge) ......

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) i Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Systemic antibiotics versus topical treatments for chronically discharging 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

ABSTRACT

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).

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

PLAIN LANGUAGE SUMMARY

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.

BACKGROUND a perforation from a previous episode of acute otitis media; or an ear with a persistent perforation with active chronic otitis media Chronically discharging ears associated with underlying persistent with metaplastic changes to the mucosa of the middle ear and mas- eardrum perforations (chronic suppurative otitis media, CSOM) toid air cell system (Browning 2003, personal correspondence). In are a common cause of preventable hearing impairment world- adults, the majority of patients are likely to have CSOM with a wide, particularly in low and middle-income countries (McPher- perforation that will not spontaneously heal. son 1997; WHO 1998). CSOM usually occurs in the first five years of life (although it often persists into adulthood), and is re- What are the effects of CSOM? lated to poor socio-economic conditions. Therefore, while this re- Hearing impairment, aside from the disability from recurrent ear view aims to address the global perspective of CSOM, much of discharge, is the most frequent effect of CSOM. A school survey the information discussed here relates to low-income settings and in Kenya found 63% of ears with CSOM had more than 30 deci- may differ in developed countries (e.g. age distribution). bels hearing loss, compared to only 3.4% of ears without outer or middle ear pathology (Hatcher 1995). Hearing impairment due What is CSOM? to otorrhoea and a perforated eardrum will usually improve as the CSOM is one of several types of otitis media (infection of the disease resolves. However, untreated CSOM may result in perma- middle ear). The World Health Organization defines CSOM as nent hearing loss due to damage to the ossicles which transmit “a stage of ear disease in which there is chronic infection of the sound vibrations from the eardrum to the cochlea. Because otitis middle ear cleft, a non-intact tympanic membrane (i.e. perforated media occurs mostly in children during pre-school years, the years eardrum) and discharge (otorrhoea), for at least the preceding two in which the most dynamic phase of speech and language develop- weeks” (WHO 1998), although this could more strictly be con- ment occurs, there is concern that the associated hearing deficits sidered a childhood definition. Perforations and infection can be may result in speech and language delays or permanent learning in one ear (unilateral) or both (bilateral). A variety of underlying disabilities, as well as disturbances in behaviour (Klein 2001). pathologies can cause CSOM including: an acute episode of acute otitis media that has burst the ear drum and not settled within In addition to hearing impairment (with its associated conse- two weeks; a recurrent episode of acute otitis media in an ear with quences), complications of otitis media can often result in death or

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 2 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd severe disability, especially in low-income countries (WHO 2000), exposure to tobacco smoke, overcrowding, attendance at day care where immunity, housing conditions, and access to medical ser- centres, lack of breastfeeding, or poor nutrition or hygiene; and vices are often poorer than in high income settings. The infec- host factors such as altered immunity and underlying diseases (e.g. tion may extend and spread to the head and neck structures and HIV/AIDS (Barnett 1992; Singh 2003), frequent upper respira- to the brain. Intracranial infections include meningitis, abscesses, tory tract infections), early onset of otitis media in the first months hydrocephalus, or thrombosis of the lateral venous sinus (from of life, and family history of otitis media. Some populations are suppuration within the mastoid causing clots occluding the lumen at increased risk of developing CSOM, and have high rates re- of the vessel) (Ludman 1997). Alternatively complications may ported, including certain ethnic groups (such as Native American be extracranial, such as subperiosteal abscess (superficial accumu- tribes of Apache and Navajo, Australian Aborigines, and Inuits of lations of pus that have broken the bony mastoid cortex), facial Canada, Greenland and Alaska), and individuals with anatomical paralysis, cholesteatoma (a destructive formation of layers of ker- defects (e.g. cleft palate or submucous cleft), altered physiologi- atinising epithelium, accumulating in the middle ear and mastoid cal defences (Eustachian tube dysfunction) or Down’s syndrome (Bluestone 1996), also described as ’active squamous (epithelial) (Bluestone 1998). chronic otitis media’ (Browning 1997)), labyrinthitis (extension What management approaches are there? to the labyrinth through the round window), or acute mastoidi- The aims of treatment are to stop the discharge (and to eradicate tis (spread of the infection to the mastoid air cells), which may infection), to heal the tympanic membrane, improve hearing, pre- spread further due to necrosis of the bony wall of the cells resulting vent the common problems of recurrent or new infections, and to in further life-threatening complications (Dhillon 1999; Ludman prevent potentially life-threatening complications. Treatment op- 1997). tions for uncomplicated CSOM include dry mopping, ear wick- How much of a burden is CSOM? ing, gentle syringing, or suctioning, to clean the ear discharge (au- Around 91% of the burden of otitis media (all types) and nearly ral toilet); systemic antibiotics (e.g. oral antibiotic preparations, all related deaths occur in low and middle-income countries or intravenous antibiotics); and topical treatment with either an- (WHO 2002; World Bank 1993). Reliable data on prevalence of tiseptics or antibiotics, sometimes with steroids. If complications CSOM are uncommon. One study estimated it at 1.1% in Kenyan develop, surgery is usually required to remove the infected tissue schoolchildren (Hatcher 1995) and a review of school and com- from the middle ear and mastoid air cells, and possibly repair the munity-based studies reported a prevalence between 0.4% and damaged eardrum and ossicles. Each of these treatments will be 6.1% in low and middle-income countries (Berman 1995). Data considered in the following Cochrane reviews: from the World Health Organization and World Bank suggest • aural toilet: aural toilet versus no treatment or various methods the global burden of otitis media (of all types) has dropped dra- of aural toilet matically since 1990, to approximately 6000 deaths (0.01% of all deaths) and 1,474,000 disability adjusted life years (DALYs) lost • systemic antibiotic treatment: systemic antibiotics versus no treat- (0.1% of all DALYs) worldwide in 2001 (WHO 2002). Most of ment or aural toilet, or various methods of systemic antibiotics these deaths are likely to be due to chronic otitis media and its • topical antiseptics: topical antiseptic versus no treatment or aural complications, because acute otitis media is usually a self-limiting toilet, or various topical antiseptics infection (Acuin 2004). • topical antibiotics without steroids: topical antibiotic, versus no Although most of the background literature cited in this review treatment or aural toilet, topical antiseptics or various topical relates to children, reliable and generalisable data for the global antibiotics, excluding steroids (Macfadyen 2005b) burden in children are not readily available; the WHO estimates therefore quoted here are for both adults and children. • systemic versus topical treatments for CSOM (THIS REVIEW): any systemic treatment against any topical treatment excluding What are the causes of CSOM? steroids The causes and risk factors associated with CSOM are unclear, and few studies have examined these for CSOM. Instead authors • systemic or topical steroids: steroids, as monotherapy or combi- have extrapolated results of studies for acute otitis media and otitis nation therapy, versus no treatment or aural toilet, topical an- media with effusion to CSOM. However, these studies often have tiseptics, topical antibiotics, or systemic antibiotics conflicting findings, and there is no proven correlation between • surgical treatment: surgery versus no treatment or any other treat- the various host and environmental factors associated with CSOM ment and the factors associated with acute otitis media and otitis me- dia with effusion. Despite this, some important factors that may A report of a WHO/CIBA Foundation Workshop held in 1996, be associated with CSOM include: environmental factors such as recommends administration of topical (and/or systemic) antibi- inadequate treatment (of CSOM and acute otitis media), poor otics as well as dry mopping/wicking, since wicking alone is felt to access to medical care, poor socioeconomic conditions, season, be ineffective (as found by Smith 1996) (WHO 1998). However,

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 3 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd the WHO guidelines still currently recommend treating CSOM • Healing of perforation at 2 to 4 weeks, and after 4 weeks by using wicking to dry the ear alone (and a five-day follow up). • Time to resolution of CSOM as defined by the investigators Systemic versus topical treatment • Improvement in hearing threshold, as measured by audiometry A number of topical antibiotics and antiseptics have been used at 2 to 4 weeks, and after 4 weeks in the treatment of CSOM. However, concern exists regarding their ability to penetrate the middle ear and mastoid cavities as • Time to re-appearance of discharge and perforation after its well as their activity against the causative bacteria (usually gram- previous resolution negative). There also remains controversy and uncertainty about • the possible ototoxic effect, in particular of topical aminoglycoside Adverse events that antibiotics (by damaging the hair cells in the basal turn of the a) are fatal, life-threatening, require inpatient hospitalisation or cochlea), particularly where the eardrum is not intact. For this prolongation of existing hospitalisation, or result in persistent or reason, systemic treatments are still often recommended and used significant disability/incapacity, such as permanent hearing loss, in preference over topical antibiotics, where the eardrum is not tinnitus or vertigo (Karbwang 1999; UMC 2003) intact. However, topical treatment may be superior to systemic b) result in withdrawal or discontinuation of treatment treatment in terms of efficacy and also safety, although this needs c) any other adverse events, such as ear pain, ear canal reactions investigating, particularly as systemic antibiotics are often more and transient dizziness easily available and remain widely used in many low and middle- income settings. 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. OBJECTIVES

To compare the effects of systemic and topical treatments (exclud- SEARCH METHODS FOR ing steroids) for chronically discharging ears with an underlying IDENTIFICATIONOFSTUDIES eardrum perforation (CSOM) in participants of any age. See: Cochrane Ear, Nose and Throat Disorders Group methods used in reviews. CRITERIAFORCONSIDERING The Trials Search Co-ordinator of the Cochrane ENT Group STUDIESFORTHISREVIEW carried out an independent search in August 2003 and March 2005. Types of studies We attempted to identify all relevant studies regardless of Individual randomised controlled trials. language or publication status (published, unpublished, in press, Cluster randomised controlled trials. and in progress). Trials reported in conference proceedings or on Types of participants posters have not been sought for this review, but will be sought for inclusion in an update of this review. People of any age with a diagnosis of CSOM as defined by the trial authors. We searched the Cochrane ENT Disorders Group Specialised Register (code SR-ENT), and the Cochrane Central Register Types of intervention of Controlled Trials (CENTRAL), published in The Cochrane Intervention: any systemic treatment excluding steroids. Library Issue 1, 2005, for relevant trials up to March 2005. Full Comparator: any topical (aural) treatment excluding steroids. details of the Cochrane ENT Disorders Group methods and the (Treatments containing steroids will not be included here, but will journals handsearched are published in The Cochrane Library in be considered in a separate Cochrane review, as indicated above). the section on Collaborative Review Groups. Comparisons may also include systemic or topical treatment versus CENTRAL was searched using the following terms: a combination of systemic and topical treatment. #1 OTITIS MEDIA SUPPURATIVE single term (MeSH) Types of outcome measures #2 OTITIS MEDIA explode all trees (MeSH) Primary #3 otitis media #4 #2 OR #3 • Resolution of CSOM at 2 to 4 weeks, and after 4 weeks, ac- #5 SUPPURATION explode all trees (MeSH) cording to the investigators’ criteria #6 suppurat* OR purulen* OR PUS Secondary #7 #5 OR #6

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 4 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd #8 #4 AND #7 • mRCT (Metadatabase of registers of ongoing trials accessible #9 CHRONIC DISEASE explode all trees (MeSH) via the Internet: http://controlled-trials.com/mrct/) #10 CHRONIC* OR PERSIST* • ENT Disorders Group Trials Register for any relevant abstracts #11 #9 OR #10 from conference proceedings #12 #1 AND #11 #13 #8 AND #11 • Reference lists of all articles/trials identified by the above #14 #12 OR #13 methods (includes searching of bibliographies for relevant #15 CHRONIC* NEAR DISCHARG* citations) #16 PERSIST* NEAR DISCHARG* • Previous published Cochrane Review, ’Interventions for #17 #15 OR #16 chronic suppurative otitis media’ (Acuin 1998) #18 #4 AND #17 #19 CSOM OR OTORRH* OR OTORH* • Other previously published (systematic) reviews: ’Chronic #20 #14 OR #18 OR #19 suppurative otitis media’, in Clinical Evidence (Acuin 2004), #21 MASTOIDITIS single term (MeSH) and ’Systematic Review of Existing Evidence and Primary Care #22 MASTOIDITIS Guidelines on the Management of Otitis Media (Middle Ear #23 TYMPANIC MEMBRANE PERFORATION single term Infection) in Aboriginal and Torres Strait Islander Populations, (MeSH) March 2001 (Couzos 2001) #24 EAR* NEAR DRUM* OR EARDRUM* OR TYMPANIC • DARE using issues 2 and 3 of the Cochrane Library 2003 - #25 PERFORAT* OR RUPTUR* searched for systematic reviews #26 #24 AND #25 #27 #20 OR #21 OR #22 OR #23 OR #26 We will explore the following potential sources of trials for future #28 ANTI-INFECTIVE AGENTS explode all trees (MeSH) updates of this review: #29 ACETIC ACID explode all trees (MeSH) • Other previously published (systematic) reviews identified by #30 BORIC ACIDS explode all trees (MeSH). the above search strategy. #31 antibiot* OR antibact* OR antisept* OR antiinfect* • OR microbides OR bacteriocid* OR antimicrobial* OR Organisations and individual researchers working in the field antimycobact* of otitis media (including authors of published trials and other #32 anti NEXT biot* OR anti NEXT bact* OR anti NEXT experts who may know about additional trials). sept* OR anti NEXT infect* OR anti NEXT mycobact* OR anti • Pharmaceutical companies (see published notes for list of NEXT microbial* companies contacted) to locate additional studies, unpublished #33 borax OR boric OR hydrogen peroxide OR iodine OR data, confidential reports, and raw data of published trials. acetic acid OR burow* OR acetate* OR acetyl #34 #28 OR #29 OR #30 OR #31 OR #32 OR #33 #35 #27 AND #34 METHODSOFTHEREVIEW #36 OTITIS-MEDIA-SUPPURATIVE-QT.DE. #37 #35 OR #36 Eligibility assessment Carolyn Macfadyen (CM) and Jose Acuin (JA) independently We also searched the following electronic databases using the reviewed the titles and abstracts identified by the search strategy search terms provided above, in combination with the search to identify potentially relevant trials. strategy for identifying trials developed by The Cochrane CM retrieved the full papers for all potentially relevant studies, Collaboration (Clarke 2003). and assessed their eligibility to be included in the review using an eligibility form based on the stated inclusion criteria. We identified (1) MEDLINE (January 1951 to March 2005) multiple publications from the same data set and reported these (2) EMBASE (January 1974 to March 2005) as one trial. Where outcomes are not reported, we contacted the (3) LILACS (www.bireme.br; January 1982 to March 2005) author of the paper for this information, as the data may have (4) AMED (1985 to March 2005) been collected but not reported. We excluded studies that do not (5) CINAHL (January 1982 to March 2005) meet the inclusion criteria for this review and stated the reason (6) OLDMEDLINE (January 1958 to December 1965) in the ’Characteristics of excluded studies’. Where necessary, we (7) PREMEDLINE contacted the study authors for clarification. (8) NNR (9) ZETOC JA and Carrol Gamble (CG) provided a second opinion on trials CM had selected for inclusion, and the three authors resolved any We searched the following potential sources of trials: disagreements through discussion.

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 5 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Assessment of methodological quality In studies that enrolled people with otitis externa, draining surgical CM assessed the methodological quality of all the trials identified cavities or acute otitis media, as well as CSOM, we only included as eligible for inclusion. CG reviewed trials where there was any the results for just CSOM participants if the authors reported ambiguity about the methods used, and JA provided further accounting for diagnosis at randomisation (e.g. stratified by information where this had already been obtained from authors diagnosis) and presented results by diagnosis. Where information of trials included in the previous review ’Interventions for chronic was not reported regarding whether alternative diagnostic groups suppurative otitis media’ (Acuin 1998). Any disagreements were were accounted for at randomisation, we included all participants resolved through discussion. Where necessary, we contacted the (groups may be unbalanced, and decisions by trialists to report study authors for further clarification. subgroups may have been linked to trend). We also included all participants where separate results were not available. See We assessed the methodological quality of the trials in terms additional Table 03 for details. For crossover trials, we have only of generation of allocation sequence, allocation concealment, taken the results before participants were crossed over to the blinding and inclusion of randomised participants. We classified alternative treatment, where possible; otherwise results for all generation of allocation sequence, allocation concealment, and participants combining pre- and post-crossover data were used. inclusion of randomised participants as adequate, inadequate and unclear as outlined by Juni 2001. Blinding is classified as double For binary data, we combined trials using relative risks (RR) blind, single blind, or open. and 95% confidence intervals (CI). We combined trials with continuous data using the weighted mean difference and its 95% Data collection confidence interval. Where data have been reported using medians CM extracted data of study characteristics, including methods, and ranges, or there is evidence of skewed data, we reported participants, interventions, and outcomes, and recorded these on medians and ranges where possible (dividing mean by the standard standard forms. JA provided further information where this had deviation; results of < 1.64 indicate a positive skew). If continuous been obtained from authors of trials included in the previous data were reported using geometric means, we combined the review ’Interventions for chronic suppurative otitis media’ (Acuin findings on a log scale and report on the original scale. 1998). In studies where data were insufficient or missing, we contacted the authors of the original studies for additional data Quinolone (e.g. ciprofloxacin) and non-quinolone antibiotics and/or verification of methods, to clarify any uncertainties about (e.g. gentamicin) are presented as separate subgroups within each the data and the way in which they were collected, and to try to comparison, but not combined across trials. This was done as there obtain missing data. is a clinical interest in the difference in effectiveness of quinolones compared to non-quinolones, as quinolones are thought to be CSOM can occur in one or both ears for each participant, which more effective and safer but more expensive. means participants can be counted more than once if ears are used as the unit of analysis. Where outcomes were reported in number Where heterogeneity is considered to be present, and it remained of ears only, we also attempted to obtain the values for number clinically appropriate to combine data, we also used DerSimonian of participants; numbers of ears were used where this information & Laird random effects model, and reported both fixed and could not be obtained. We checked the data and resolved any random effects results. discrepancies by referring to the trial report, through discussion. The primary analysis is of all eligible studies. If a sufficient number Where possible we extracted data to allow an intention to treat of trials is available for future updates (not available for each analysis (i.e. the analysis should include all the participants in the comparison in this version of the review), we will explore whether groups to which they were originally randomly assigned). If the heterogeneity can be explained using subgroup analyses or meta- number randomised and the numbers analysed were inconsistent, regression for the following factors: age (under 16, and adults 16 we calculated a percent loss-to-follow-up and reported this years or older), associated mopping (dividing studies into those information in additional Table 01. For binary outcomes, we with some form of ear toilet, and those without), co-interventions recorded total number of participants (or ears, where participant (dividing studies into those with treatment comparison alone, numbers were unavailable) and number with the event in each and those with treatment comparison in combination with other group of the trial. For continuous outcomes, for each group, we co-interventions), and methodological quality (initially excluding extracted the number of participants, and the arithmetic means studies of the poorest quality). Sensitivity analyses will also and standard deviations. If the data were reporting using geometric be used to explore methodological quality (notably adequate means, we planned to extract standard deviations on the log scale. concealment), and trial design (e.g. cluster randomisation). We We planned to extract medians and ranges, and report these in will display the results for each sensitivity analysis according to the additional tables if any trials reported these. subgroups within each methods category.

Data analysis The sensitivity analysis will include the following, as outlined in CM entered data into Review Manager 4.2. the statistical guidelines in the Cochrane ENT Group Guidelines

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 6 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd for Reviewers (CochraneENTGuideline updated November The Characteristics of Excluded Studies Table outlines reasons for 2000). excluding studies following review of their full texts. The Charac- teristics of Included Studies Table provides information on the in- (1) Repeat the analysis excluding unpublished studies (if any). cluded trials; also see additional tables: Table 01 (methodological (2) Repeat the analysis excluding studies of the lowest quality quality of included studies); Table 02 (bilateral disease - numbers (already done if there is heterogeneity). for ears and participants); Table 03 (participant eligibility criteria, (3) If there are one or more very large studies, we will repeat the including CSOM diagnostic criteria); Table 04 (intervention reg- analysis excluding these, to investigate how much they dominate imens used); Table 05 (outcomes assessed). the results. (4) Repeat the analysis excluding studies where people with CSOM Age, setting and location (for included studies) are only a subgroup of the participants included in the study, See the Characteristics of Included Studies table for details. for example, those that enrol people with otitis externa, draining Ages varied surgical cavities or acute otitis media, as well as CSOM. • All studies included adults; four also included participants less Within this version of the review, trials where people with CSOM than 16 years old (with minimum ages between 6 and 15 years). are only a subgroup of the participants included in the study are Details are reported in the characteristics of included studies identified - see additional Table 03. table and additional Table 03. For this version of the review, we visually examined forest plots, Setting in conjunction with the chi2 test, using a 5% level of statistical significance, and the I2 statistic. The I2 statistic describes the • No studies were reported to be community-based trials. percentage of the variability in effect estimates that is due to • Four were hospital based (ENT/outpatient departments); five heterogeneity rather than sampling error (chance). A value greater did not specify but also appear to hospital/clinic based. than 50% may be considered substantial heterogeneity (Deeks 2004). There were insufficient trials to investigate publication bias Location using funnel plots; this may be done in further updates of the • Eight trials were in high-income countries (UK, Italy, Spain, review. Gran Canaria, Greece and Hong Kong). • One trial was in a low- or middle-income country (Thailand). DESCRIPTION OF STUDIES Diagnostic criteria for included participants Additional Table 03 provides eligibility criteria and more detailed Search results CSOM diagnostic criteria. Definitions used for CSOM varied, The electronic searches identified 649 citations in August and particularly for duration, and also whether positive bacterial cul- September 2003, plus 698 citations in March 2005, including ture or changes in mucosal appearance were assessed and/or re- four unpublished trials. Three additional trials were already known quired - see additional Table 03. We accepted the authors’ defini- to the authors: van Hasselt 1997; van Hasselt 1998; van Hasselt tions when assessing eligibility. 2002. Macfadyen 2005a was also undertaken by two of the au- thors. Trials with duplicate publications were identified and re- Four trials included cases with otorrhoea following mastoidectomy ferred to under the main trial publication. Full texts of 127 trials (Browning 1983; Mira 1992; Papastavros 1989), tympanoplasty were reviewed, and nine included as eligible for this review - see (Mira 1992), or other surgery (de Miguel 1999). Two included os- breakdown of numbers below. We attempted to include all rele- teitic or cholesteatomatous disease (de Miguel 1999; Papastavros vant studies regardless of language. 1989). Papastavros 1989 also included participants with a posi- tive fistula sign and additional symptoms of complications. Papas- • 127 trials: Full texts obtained for eligibility assessment (117 tavros 1989 gave separate results for simple tubotympanic mucosi- from the above sources, plus ten from reference lists and other tis and atticoantral disease but not for any other findings. How- searches). Of these, 85 were in English only, three had English ever, randomisation does not appear to be stratified by diagnosis and non-English publications, and 39 were in non-English lan- and all participants are included in this review. No other results guages only. were reported separately for any trial, and all participants are in- • 112 trials excluded: 79 English only, two English and non- cluded in this review for these remaining trials. Additional Table English language, 31 only available in non-English language. 03 provides further details with numbers involved. • Six trials only available in non-English language, awaiting trans- Interventions lation to determine eligibility. Additional Table 04 provides details of the treatment regimens used in the trials. The following treatments were assessed: • Nine trials included: six English only, one English and non- English language, two only available in non-English language. Topical antiseptics - two trials

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 7 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd • Boric acid and iodine powder (Browning 1983), and borax pow- for failures after two to three weeks (Papastavros 1989); pre- and der or hydrogen peroxide drops (randomly allocated; Papas- post-crossover numbers were not reported separately, and all cases tavros 1989). have been included in this review. Systemic antibiotics alone - eight trials Outcomes The Characteristics of Included Studies Table indicates which re- • Two allocated one of a range of antibiotics within the treatment view outcomes were covered by each trial. Additional Table 05 de- arm, according to bacteriology: scribes the definitions used by the trials, for each review outcome, *Browning 1983 used oral non-quinolones: penicillins (flu- and how and when outcomes were measured and reported. cloxacillin, cloxacillin, amoxicillin) and cephalosporins (oral Treatment failure (persistent discharge) - eight trials cephalexin); participants with Pseudomonas species were not ran- Eight trials reported CSOM resolution for inclusion in the pri- domised to this group, due to resistance. mary outcome of this review. However, definitions varied, and *Papastavros 1989 used a range of: oral and intravenous non- most only reported results before two weeks - see Table 05. Where quinolones [penicillins (oral amoxicillin plus clavulanate; intra- trials reported separate categories for ’cure’ and ’improvement’, we venous piperacillin), macrolides (oral erythromycin), beta-lac- have classed ’improvement’ as failure along with any other cases tam (intravenous aztreonam, Azactam), and other non-quinolones of failure reported. (oral metronidazole, or sulfamethoxazole plus trimethoprim)]; oral quinolones (ciprofloxacin); and quinolone plus non- One further trial reported assessing an outcome in this category, quinolone (oral ciprofloxacin plus metronidazole). but did not provide sufficient results for this review (Mira 1992). • The other six trials tested four different systemic antibiotics Healing of the perforation - no trials: alone: Yuen 1994 reported assessing the perforation size during the study * Three tested non-quinolones: oral penicillin (amoxicillin plus but did not provide results after treatment. Supiyaphun 2000 also clavulanate, Augmentin); intramuscular aminoglycoside (gentam- reported baseline perforation size but no subsequent results. icin sulfate); intramuscular cephalosporin (ceftizoxime). Time to resolution of CSOM - no trials * Three tested quinolones: oral ciprofloxacin. Improvement in hearing threshold - one trial: Topical antibiotics alone - seven trials See additional tables for Supiyaphun 2000: Table 07 for changes • Six tested topical quinolones: four ciprofloxacin, two ofloxacin. in bone conduction and speech reception threshold, Table 08 for ototoxic rate, and also Table 06 for a summary statement for oto- • One tested topical non-quinolones: aminoglycoside (gentam- toxicity. See also figure (comparison 04, outcome 01, subgroups icin) or chloramphenicol, according to bacteriology (Browning 02 and 03). 1983). Four other trials assessed hearing, but only reported a summary Systemic plus topical antibiotics combined - four trials statement regarding lack of change (Yuen 1994) or worsening • Two tested non-quinolones: one intramuscular plus topical in hearing or ototoxicity. Additional Table 06 (safety) provides cephalosporin (ceftizoxime); one oral penicillin (amoxicillin) information regarding worsened hearing, where available. plus topical chloramphenicol. Time to reappearance of discharge and perforation after its previous • Two tested quinolones: oral plus topical ciprofloxacin. resolution - no trials However two trials reported absence of relapses two to three weeks Placebo - two trials after treatment (Esposito 1990 and Esposito 1992). • One topical (normal saline) and one systemic. Adverse events - six trials Most trials disallowed other treatments for a period before and/or Results of ototoxicity assessments and other adverse events col- during the study - see Table 04 for details and exceptions. Treat- lected are reported in additional Table 06 (safety). One further ment duration was usually between 5 and 14 days; two trials gave trial reported monitoring safety but did not provide results (Pa- treatment for longer. Three studies did not mention aural toi- pastavros 1989). let (Esposito 1990; Esposito 1992; Povedano 1995); the rest ap- Other outcomes assessed but not specified in the protocol for this review peared to be comparable across groups, performing aural toilet for - nine trials all groups (usually suction/aspiration) either before the first dose See additional Table 05 for details of these outcomes, which have only or as necessary at each visit. However, further information not been analysed in this review. has been requested from authors of all trials to confirm the aural toilet regimen. See Table 04 for more details of treatment regi- Sources of support mens. One trial included a crossover to the alternative treatment Pharmaceutical company support - one trial (Supiyaphun 2000).

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 8 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Two trials further reported provision of treatment by pharmaceu- Two trials each reported only one dropout but did not provide tical companies (Esposito 1990; Esposito 1992). the actual numbers or totals analysed for the results, to confirm University committee grant - one trial (Yuen 1994). whether adequate numbers were included in the analysis (Mira Not mentioned - seven trials. 1992 and Supiyaphun 2000).

One was “inadequate”: METHODOLOGICALQUALITY One trial reported 32% dropout for defaulters or non-compliers (Browning 1983 - see Table 01).

Additional Table 01 provides details of the methodological quality Main reasons specified for exclusion were: of included studies. Non-compliance (used <75% of the medication: Browning 1983); Sequence generation lack of attendance (loss to follow-up: Mira 1992; Supiyaphun Two were “adequate”: Mira 1992; Yuen 1994. 2000; Yuen 1994); adverse event (Yuen 1994). One was “inadequate”: Papastavros 1989 - six high risk compli- Bilateral disease cated cases were allocated to systemic antibiotics, and not ran- Most trials analysed and presented results by participant, although domised (results not presented separately). The remaining partic- some reported ears instead, and most did not explain how bilat- ipants were described as randomised, but did not discuss how se- eral disease was treated or analysed. Additional Table 02 provides quence was generated, or how different diagnoses were accounted detailed information regarding bilateral disease, and reporting of for during randomisation. ears versus participants, for each trial. Where available the number of participants with bilateral disease for each trial is also presented. Six were “unclear”: described as randomised, but did not discuss Clarification has been requested from the authors for further in- how the sequence was generated, or how different diagnoses were formation on handling bilateral cases and where numbers analysed accounted for during randomisation. and totals for the results are unclear.

Allocation concealment Results for ears - two trials One was “adequate”: Yuen 1994 (drawing concealed envelopes). For bilateral disease each ear was treated and analysed as a separate Eight were “unclear”: allocation concealment was not discussed case. Rates of bilateral disease in these trials were 32% (Papastavros (three trials were described as single blind). 1989) and 12.7% (Supiyaphun 2000). However, Supiyaphun 2000 reported results as percentages of ears Blinding with no actual numbers or totals, and rates reported do not equate Three trials were single-blind; six did not report on blinding. to whole ears when using the total numbers of ears excluding Balance of baseline characteristics across groups dropouts (rates sometimes match number of participants more This was not reported in one trial. The rest reported at least one closely). See additional Table 02. characteristic by treatment group - see additional Table 01 for Results for participants - seven trials details. However, Mira 1992 reported overall scores without actual num- For the four trials that included a range of diagnoses, Mira 1992 bers or totals. reported numbers for each across treatment groups and was mostly Only one trial specified how bilateral cases were handled (Brown- balanced; Papastavros 1989 reported type of disease (balanced), ing 1983). See additional Table 02. but did not report other complications by group except the six Where available, we have reported results for number of partici- non-randomised complicated cases on systemic treatment, giving pants rather than ears; otherwise results for number of ears have a higher morbidity in this group. Browning 1983 and de Miguel been taken. The concern is that a trial analysed by ears rather than 1999 did not present baseline numbers or results for each diagnosis number of participants will have an underestimated standard error separately by treatment group. and therefore receive an inappropriate increased weight in a meta- Follow up (inclusion of randomised participants) analysis. We will use the information in Table 02 to attempt to For the primary outcome, resolution or treatment failure: address the issues of inflated weighting for trials reporting num- bers of ears, in a later update of this review. 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 RESULTS follow-up or exclusions. Yuen 1994 reported a 7% (4/60) dropout rate - see Table 01. See also additional tables (Table 02 for details regarding bilateral Two were “unclear”: disease in each trial, Table 04 for details of the treatment regimens

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 9 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd used for each of the sets of comparisons discussed below, and Ta- chloramphenicol or gentamicin to a variety of systemic penicillins ble 05 for the definitions and timings of the outcomes assessed or cephalosporin, treatment in both groups depending on base- by trialists for each outcome category). Data relating to adverse line bacteriology results. Both groups received weekly aural toilet events and ototoxicity have been summarised in additional Table and suction aspiration when necessary. Results were presented for 06 for trials that mentioned this outcome. We have only presented participants. outcomes below that the trial authors have reported - see Table 05 for other outcomes. Clarification is being sought from the authors Treatment failure (Figure: comparison 02, outcome 01, subgroup 01) where uncertainties exist in the data and where outcomes are not Results after four weeks (end of treatment) showed a trend in reported. These responses will be incorporated in subsequent up- favour of systemic antibiotics, although this crossed the line of no- dates of the review. effect: RR (95% CI) 0.74 (0.46 to 1.19). There were insufficient trials in each comparison to consider ex- Comparisons between topical quinolones and systemic non- ploring heterogeneity or the sensitivity analyses outlined above; quinolones these will be considered in a subsequent update of the review Two trials compared topical quinolone antibiotics alone with sys- if there are sufficient trials. Meanwhile, trials where people with temic non-quinolones alone (Esposito 1992 and Yuen 1994). Es- CSOM are only a subgroup of the participants included in the posito 1992 did not mention aural toilet, while Yuen 1994 gave study are identified in this review - see additional Table 03. suction cleaning before the first dose only (both groups). Both trials reported results at the participant level. Do topical antiseptics work better than systemic antibiotics? Two trials compared topical antiseptics to systemic antibiotics: Treatment failure (Figure: comparison 02, outcome 01, subgroup 02) Browning 1983 compared topical antiseptic given once weekly The results reported for Esposito 1992 appear to be for 12 hours with daily systemic antibiotics. Although not stated in the trial after five to ten days treatment, while Yuen reported results at week report, the authors confirmed that aural toilet was given in all two. The pooled results showed a significant effect in favour of groups (weekly aural toilet by the otologist, using microscopic vi- topical quinolone: RR (95% CI) was 3.21 (1.88 to 5.49). sion, and suction aspiration when necessary). Results were pre- No longer-term data were reported, although Esposito 1992 re- sented for participants, and also included those with draining mas- ported that all participants who were clinically and bacteriologi- toid cavities. Papastavros 1989 used a variety of antiseptics and cally cured 12 hours after five to ten days treatment, confirmed antibiotics (non-quinolone and quinolone) and also performed their clinical status 14 and 21 days later; no relapses were observed. toilet and debridement of the ear with suction as necessary for A request has been made to the authors to confirm the total num- both groups, performed at regular visits. Results were reported for bers at each occasion, and whether any additional cures were ob- ears, and include both pre- and post-crossover data. served. In both trials, the choice of antibiotics depended on baseline bac- teriology results. Healing of the perforation Esposito 1992 did not mention this outcome, while Yuen 1994 Treatment failure (persistent discharge) (Figure: comparison 01, out- reported measuring size of perforation at each visit but did not come 01) provide any results; a request has been made to the authors for any Browning 1983 presented results after four weeks treatment. Clar- available results. ification has been sought from the authors of Papastavros 1989 for whether the results presented are after ten days or two to three Improvement in hearing threshold weeks treatment. Results for all diagnoses did not demonstrate any Esposito 1992 measured audiometry and vestibular tests before statistically significant difference between groups: the RR (95% and 24 hours after treatment but only provided a summary state- CI) is 0.81 (0.61 to 1.08) in favour of antibiotics. ment that “no worsening of the audiometric function related to lo- cal or parenteral therapy was observed”. Yuen 1994 measured pure Adverse events tone audiometry, reporting for bone conduction at four frequen- Browning 1983 did not mention this outcome; Papastavros 1989 cies from 0.5 to 4kHz, but only reported a summary statement collected details of systemic adverse effects and appearance of com- that “there were no significant differences between the pre- and plications or bothersome allergic reactions but results were not re- post-treatment pure-tone audiograms of bone conduction thresh- ported. A request has been made to the authors for any available olds...” See additional Table 06 for both trials. A request has been results. made to the authors for the results to be made available.

Do topical antibiotics alone work better than systemic antibi- Adverse Events otics alone? Data relating to adverse events have been summarised in additional Comparisons between topical and systemic non-quinolones Table 06. One trial compared topical non-quinolone antibiotics alone to systemic non-quinolones alone: Browning 1983 compared topical Comparisons between topical and systemic quinolones

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 10 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Three trials compared topical and oral ciprofloxacin (Esposito Treatment failure 1990; Povedano 1995; de Miguel 1999). de Miguel 1999 in- Mira 1992 assessed the overall clinical course of disease (accord- cluded two treatment groups assessing topical ciprofloxacin alone ing to fever, symptoms of infection and negative culture) but did (at 0.2% and 0.5% strengths), for comparison with the treatment not provide results. In a summary statement, the authors reported group receiving topical plus oral ciprofloxacin - results for both that there was no difference between the two groups of partici- strengths are presented in this review. Only de Miguel 1999 dis- pants for the overall judgement expressed by the investigating doc- cussed aural toilet, cleaning the ears by aspiration before starting tors, although a slightly higher success rate was recorded in the treatment only. All trials reported results at the participant level. systemic plus topical treatment group. Symptom severity scores were also assessed at days 0, 3, 7 and 21, for otorrhoea, otalgia, Treatment failure (Figure: comparison 02, outcome 01, subgroup 03) oedema and congestion; however the trial report only provided No trials reported results after 2 weeks: the results reported for overall scores per group over time, with p-values, but no numbers Esposito 1990 appear to be for 24 hours after five to ten days assessed, standard deviations for average scores, or totals with each treatment; Povedano 1995 reported results after 10 days treatment; score. In a summary statement, the authors stated there was a sig- and clarification has been sought from the authors of de Miguel nificant difference in greater promptness of action using topical 1999 for whether the results relate to day 8 or 15. treatment (significant difference between treatments at day three, The pooled RR (95% CI) is 3.18 (1.87 to 5.43) in favour of top- not significant by day seven), while intramuscular treatment alone ical antibiotic over systemic treatment. This uses the combined seemed to increase the risk of repeat infection, with a resurgence of results for both topical ciprofloxacin groups in de Miguel 1999, symptoms (significant difference in favour of systemic plus topical as no difference in effectiveness for either strength had been de- treatment again at day 21). Further details have been requested tected. Taking results for just 0.2% ciprofloxacin (3/25 failed) or from the authors. 0.5% ciprofloxacin (4/25 failed) in the topical treatment group, Adverse events gives RR (95% CI): 3.33 (1.04 to 10.69) and 2.50 (0.90 to 6.92) Data relating to adverse events have been summarised in additional respectively for de Miguel 1999; and pooled results of RR (95% Table 06. 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% Adding topical quinolone to systemic quinolone and 0.5% groups respectively. Two trials compared systemic ciprofloxacin alone with systemic plus topical ciprofloxacin (de Miguel 1999 and Esposito 1990). No longer-term data were reported, although Esposito 1990 re- Only de Miguel 1999 discussed aural toilet, cleaning the ears by ported that all participants who were clinically and bacteriologi- aspiration before starting treatment only. Both trials reported at cally cured 24 hours after five to ten days treatment, confirmed the participant level. their clinical status 14 days later. A request has been made to the authors to confirm the total numbers at each occasion, and Treatment failure (Figure: comparison 03, outcome 01) whether any additional cures were observed. No trials reported results after 2 weeks: the results reported for Esposito 1990 appear to be for 24 hours after five to ten days Improvement in hearing threshold treatment, and clarification has been sought from the authors of Povedano 1995 did not report this outcome. de Miguel 1999 and de Miguel 1999 for whether the results relate to day 8 or 15. Esposito 1990 reported recording this outcome (only for partic- ipants receiving topical treatment in Esposito 1990) but neither The pooled RR (95% CI) is 2.75 (1.38 to 5.46) in favour of sys- provided results except in a summary statement reporting a lack of temic plus topical antibiotic over systemic treatment alone. No ototoxicity or related problems - see additional Table 06. A request longer-term data were reported, although Esposito 1990 reported has been made to the authors for results to be made available. that all participants who were clinically and bacteriologically cured 24 hours after five to ten days treatment, confirmed their clini- Adverse events cal status 14 days later. A request has been made to the authors Data relating to adverse events have been summarised in additional to confirm the total numbers at each occasion, and whether any Table 06. Povedano 1995 did not report this outcome; a request additional cures were observed. has been made to the authors for any available results. Improvement in hearing threshold Does adding a topical antibiotic to a systemic antibiotic im- de Miguel 1999 and Esposito 1990 reported recording this out- prove treatment? come (only for participants receiving topical treatment in Esposito Adding topical non-quinolone to systemic non-quinolone: 1990) but neither provided results except in a summary statement One trial compared systemic non-quinolone alone with systemic reporting a lack of ototoxicity or related problems - see additional plus topical non-quinolones: Mira 1992 used intramuscular and Table 06. A request has been made to the authors for results to be topical ceftizoxime. In both groups, aspiration of local secretions made available. was performed by the specialist before the fist dose only. Outcomes were assessed at the participant level. Adverse events

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 11 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Data relating to adverse events have been summarised in additional to 39.37) for bone conduction and 2.54 (0.99 to 6.53) for speech Table 06. reception threshold (see figure). Does adding systemic antibiotic to a topical antibiotic improve Other adverse events: treatment? Further data relating to other adverse events have been summarised Comparisons between systemic plus topical non-quinolone and in additional Table 06. topical quinolone alone One trial compared systemic and topical non-quinolone treat- Comparisons between systemic plus topical quinolone and top- ment (oral amoxicillin plus topical chloramphenicol) with topical ical quinolone alone quinolone alone (ofloxacin): Supiyaphun 2000. Aural toilet was Two trials compared systemic plus topical ciprofloxacin with top- performed on Day 0 only for both groups. Results were reported as ical ciprofloxacin alone (de Miguel 1999 and Esposito 1990). de percentage of ears at two weeks only. However, the actual numbers Miguel 1999 included two groups with topical ciprofloxacin alone or totals were not reported, and the rates reported do not equate (at 0.2% and 0.5% strengths) - results for both are presented in to whole ears, when taking the total numbers of ears excluding this review. Only de Miguel 1999 discussed aural toilet, cleaning dropouts. Clarification has been requested from the authors for the ears by aspiration before starting treatment only. Both trials the actual numbers and confirmation of the unit of analysis. reported at the participant level. Treatment failure at two weeks (Figure: comparison 04, outcome 01, subgroup 01) Treatment failure (Figure: comparison 04, outcome 02, subgroup 01) Results were reported for cure at two weeks only. Taking the re- No trials reported results after two weeks: the results reported for sults to the nearest whole number for ears and assuming all ears Esposito 1990 appear to be for 24 hours after five to ten days were included in the analysis, the results were: RR (95% CI) 2.74 treatment, and clarification has been sought from the authors of (1.52 to 4.94) in favour of topical quinolone antibiotic alone over de Miguel 1999 for whether the results relate to day 8 or 15. systemic plus topical non-quinolone antibiotic. A request has been made to the authors to confirm whether any data were collected The pooled results showed little difference between the systemic after two weeks, and if so, for the results to be made available. plus topical versus topical quinolone treatment alone: RR (95% CI) 1.17 (0.48 to 2.86). This uses the combined results for both Improvement in hearing threshold topical ciprofloxacin groups in de Miguel 1999, as no difference in Table 07 shows changes in audiometry for Supiyaphun 2000. In effectiveness for either strength had been detected. Taking results a summary statement, the authors reported that a significant im- for just 0.2% ciprofloxacin (3/25 failed) or 0.5% ciprofloxacin provement in bone conduction (p<0.001) and speech reception (4/25 failed) in the topical treatment alone group, gives RR (95% threshold (p=0.002) was achieved in ofloxacin treated ears. Mean- CI): 1.00 (0.22 to 4.49) and 0.75 (0.19 to 3.01) respectively for while a considerable deterioration (elevation) was observed in bone de Miguel 1999; and pooled results of RR (95% CI): 1.33 (0.50 conduction in amoxicillin plus chloramphenicol treated ears (p= to 3.52) (I2=0%, chi2 p=0.61), and 1.14 (0.45 to 2.89) (I2=0%, 0.007). The authors did not report the numbers included in these chi2 p=0.41) for 0.2% and 0.5% groups respectively. analyses and a request has been sent to the authors for this to be provided. No longer-term data were reported, although Esposito 1990 re- Adverse events ported that all participants who were clinically and bacteriologi- Ototoxicity (Figure: comparison 04, outcome 01, subgroup 02 and cally cured 24 hours after five to ten days treatment, confirmed 03): their clinical status 14 days later. A request has been made to Additional Table 08 provides the ototoxic rate per group, while the authors to confirm the total numbers at each occasion, and additional Table 06 gives a summary statement of the ototoxic- whether any additional cures were observed. ity in the systemic plus topical non-quinolone treatment group. The authors found the ototoxic rate (percentage of ears in which Improvement in hearing threshold the elevation of bone conduction or speech reception threshold de Miguel 1999 and Esposito 1990 reported recording this out- was greater than 5dB or had a high frequency hearing loss, with come (only for participants receiving topical treatment in Esposito or without tinnitus) was also significantly higher in the systemic 1990) but neither provided results except in a summary statement amoxicillin plus topical chloramphenicol group than in topical reporting a lack of ototoxicity or related problems - see additional ofloxacin treated ears, which they attributed to the chlorampheni- Table 06. A request has been made to the authors for results to be col. The authors did not report the numbers included in these made available. 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 Adverse events number for ears and assuming all ears were included in the analysis Data relating to adverse events have been summarised in additional and results presented, the findings are RR (95%CI): 9.78 (2.43 Table 06.

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 12 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd DISCUSSION tibiotics were compared to topical quinolones (Supiyaphun 2000). No trials found a statistically significant effect in favour of keep- We excluded trials or comparisons with steroids (with or without ing systemic antibiotic in the treatment regimen. This is a useful antibiotics; see steroids review), and presented findings for top- finding, given the added cost and likely reduced adherence when ical antiseptics, topical antibiotics, and systemic plus topical an- using a combination of treatments instead of monotherapy. tibiotics separately, to address focused and meaningful questions. These tighter comparisons and addition of new trials are why Systemic adverse effects noted by the authors included gastric com- minimal heterogeneity was observed in the comparisons presented plaints and one case of skin rash. Topical effects were mainly local, here and why some of our conclusions differ to those of an earlier including fungal growth (otomycosis), pain on drops (37% with review (Acuin 1998). Although trials that mentioned aural toilet chloramphenicol compared to 5.1% with ofloxacin in one trial, appeared to use comparable regimens across groups, information Supiyaphun 2000), and tinnitus (one case, on oral amoxicillin is being requested from the trials authors to confirm this was in- and topical chloramphenicol, which resolved on discontinuing the deed the case, and also to obtain details for the three trials that did drops: Supiyaphun 2000). Supiyaphun 2000 also report a signifi- not discuss aural toilet at all. cant elevation (i.e. deterioration) of bone conduction and speech Two trials compared systemic antibiotic (mostly non-quinolones) reception threshold, and significantly higher ototoxic rates for par- with topical antiseptic, and did not detect any statistically signifi- ticipants receiving oral amoxicillin and topical chloramphenicol cant differences between treatment groups for clinical cure. How- (non-quinolone) than for those on topical ofloxacin (quinolone), ever the choice of antibiotic depended on bacterial results for both which was attributed to the chloramphenicol. No other trials in trials, and Browning 1983 compared daily antibiotics with weekly this review reported any worsening of audiometry results or evi- antiseptic. Results were only presented for up to three and four dence of ototoxicity. However, ototoxicity has been observed for weeks and included participants with draining mastoid cavities various non-quinolone antibiotics, and aminoglycoside antibiotics and other complications. are not recommended in patients with a tympanic membrane per- foration by the Medicines and Healthcare Products Regulatory Topical quinolone antibiotics alone were statistically significantly Agency (MHRA) in the UK (CSM 1997). One review of ototox- better than systemic antibiotics alone. This was true for non- icity cases in humans reported that ototoxicity may be primarily quinolone and quinolone systemic treatments, both of which had due to vestibular damage (causing imbalance and dizziness) rather very similar treatment effects (pooled RR (95% CI) were: 3.21 than cochlear (Marais 1998), so assessments of hearing thresholds (1.88 to 5.49) in favour of topical quinolones over systemic non- for bone conduction alone would be unlikely to detect many cases quinolones, and 3.18 (1.87 to 5.43) for systemic quinolones). (Marais 1998; Lancaster 1999). 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 The follow-up period in all trials included here was short. No gave treatment for longer and presented results later than the other trials assessed longer-term effects of treatment, or reported time trials (four weeks), was the only trial that did not find an effect in to resolution or to reappearance of discharge and perforation, or favour of topical antibiotic treatment. results for healing of the tympanic membrane. As conclusions can change over time, it may be important to investigate the longer- The effect of adding topical treatment to systemic treatment was term effects in future trials. presented in two trials, both using only quinolone antibiotics. Both reported higher cure rates at one to two weeks when topical Most of the trials in this review were poor quality, with short antibiotic was added to systemic treatment. However, the longer- follow-up. Many included a range of participants (e.g. including term results were not presented. One further trial reported a ben- otitis externa, or draining mastoid cavities, or cholesteatomatous eficial effect of adding topical antibiotic to systemic treatment, disease). This may explain some of the heterogeneity found, since using non-quinolone antibiotics, but did not provide full results resolution rates may vary widely between diagnoses, and so make (Mira 1992); further details have been requested from the authors the results less applicable to any one type of disease. Trials were also for the results of this trial. inconsistent in approaches for handling and reporting bilateral Three trials assessed the effect of adding systemic antibiotics to top- disease. Where available, we have reported results for number of ical treatment (i.e. compared topical antibiotic alone to systemic participants rather than ears; otherwise results for number of ears and topical antibiotics), all reporting results at one to two weeks have been taken. The concern is that a trial analysed by ears rather only. When using quinolones in both treatment groups (two tri- than number of participants will have an underestimated standard als), no benefit was found when adding systemic antibiotics to top- error and therefore receive an inappropriate increased weight in a ical treatment, with no statistically significant difference for cure. meta-analysis. We will use the information obtained to attempt to However, a statistically significant difference in favour of topical address the issues of inflated weighting for trials reporting numbers antibiotic was found when systemic and topical non-quinolone an- of ears, in a later update of this review.

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 13 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd AUTHORS’ CONCLUSIONS Issue review first published: 1998/4 (Interventions for chronic suppurative otitis media). Implications for practice Date of most recent amendment: Information not available. Date of most recent SUBSTANTIVE amendment: 12 February Short courses of topical quinolone antibiotics are more effective 1998. than systemic antibiotics alone for the short-term resolution of ot- Most recent changes: orrhoea from uncomplicated CSOM. The effects of topical non- February 1998. quinolone antibiotics (without steroids) or antiseptics are less clear, October 2001: Cochrane review ’Interventions for chronic sup- when compared to systemic treatment; no benefit of adding sys- purative otitis media’ split into a series of Cochrane review titles, temic treatment to topical antibiotics was detected either, although each focusing on particular interventions. evidence was limited. Less is known about longer-term outcomes (for dry ear, or to prevent complications, heal the eardrum, and Issue 1, 2004: Publish protocol for component review ’Topical an- improve hearing), or about treating complicated CSOM. Evi- tibiotics for chronically discharging ears with underlying eardrum dence regarding safety is also weak, and more research is needed perforations’. to clarify the risk of ototoxicity with alternative treatments (about DEVIATIONS FROM THE PROTOCOL which there is much concern, particularly for topical aminoglyco- The following changes were made to the eligibility criteria and sides), and whether there may be fewer adverse events with topical outcome measures from those stipulated in the protocol: quinolones than alternative topical or systemic treatments. Treat- ment should therefore be accompanied by regular medical follow- 1. ELIGIBILITY CRITERIA up and clinical vigilance, also monitoring for adverse effects of Types of studies: quasi-randomised controlled trials were specified treatment (particularly for local effects or signs of ototoxicity), or in the protocol but excluded from the review. for complications of the disease. Clinical staff should also advise Types of participants: patients and their caregivers on appropriate ear care, with aural Protocol: People of any age with a diagnosis of CSOM meeting toilet and effective instillation of the drops, ensuring the drops the WHO definition reach the site of infection to work effectively. Review: any diagnosis of CSOM as defined by the trial authors. Implications for research Types of interventions - the following were stipulated in the pro- Further trials should clarify the effects of non-quinolone antibi- tocol: otics and antiseptics. Adequately designed and powered studies Intervention: topical (aural) antibiotics (all and individual) should focus on the effects on the longer-term natural history Comparator: no intervention; placebo; other topical antibiotics of CSOM, such as healing of the tympanic membrane, hearing with and without steroids; systemic antibiotics (all and individual); improvement, prevention of complications, and also on further combination of topical and systemic antibiotics; antiseptics. safety assessments. Other more comprehensive systematic reviews However, we have divided these trials into the following three should also assess safety further, particularly to verify the risks of reviews: ototoxicity for alternative treatments. Trialists should also consider * Topical treatment with antibiotics how they handle bilateral disease and also the type of participants comparisons: no treatment or aural toilet, topical antiseptics, var- included (or stratify randomisation by diagnosis if various diag- ious topical antibiotics, excluding steroids noses are included), to ensure the results are clinically relevant to a * Systemic versus topical treatments for CSOM (THIS REVIEW) particular patient group. The cost effectiveness of alternative treat- comparisons: any systemic treatment against any topical treatment ments, preferably through economic evaluations alongside clini- excluding steroids cal trials, would be valuable in guiding both clinical practice and * Systemic or topical steroids, as monotherapy or combination health policy. therapy comparisons: no treatment or aural toilet, topical antiseptics, top- ical antibiotics, systemic antibiotics NOTES 2. OUTCOMES This review, ’Systemic vs topical treatments for chronically dis- Types of outcome measures - the following primary outcomes have charging ears with underlying eardrum perforations’ is one in a se- been changed: ries of reviews, which replaces the review ’Interventions for chronic Protocol: suppurative otitis media’. Reviews of other interventions will fol- * Resolution of CSOM at 2 to 4 weeks and after 4 weeks, according low. to the following findings: a) No report of otorrhoea REVIEW HISTORY b) Disappearance of discharge on otoscopy

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 14 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd c) Healing of the eardrum perforation on otoscopy The protocol stated that allocation concealment, and inclusion d) Time to resolution of CSOM according to any other defini- of randomised participants, would be assessed as inadequate if an tion of resolution made by the authors, including improvement allocation concealment approach was not reported, or it was not in mucosal appearance clear how many people were originally randomised into the trial, respectively. However, we have classed these as unclear. Review: * Resolution of CSOM at 2 to 4 weeks, and after 4 weeks, according We assessed the methodological quality of the trials using the fol- to the investigators’ criteria. lowing dimensions and criteria based on four methodological as- We have also analysed results for treatment failure rather than pects. success. a) Generation of allocation sequence The others were analysed as separate, secondary outcomes (where Adequate: if sequences are suitable to prevent selection bias and reported by trialists): the method used is described. * Healing of perforation at 2 to 4 weeks, and after 4 weeks; Adequate methods include random numbers generated by com- * Time to resolution of CSOM as defined by the investigators. puter, table of random numbers, drawing of lots or envelopes, The other protocol outcomes were unchanged, except that results tossing a coin, shuffling cards, throwing dice, or other methods of before 2 weeks were also included and reported separately. allocation that appear to be unbiased.

3. SEARCH STRATEGY Unclear: stated but method not described. The protocol stated that we would obtain all relevant studies re- The trial describes itself as being randomised but no further in- gardless of publication status. However, trials reported in confer- formation is given. ence proceedings or on posters have not yet been sought, but will Inadequate: if sequence could be related to prognosis. be sought for inclusion in an update of this review. Additionally, Inadequate methods include case record number, date of birth, the further potential sources that we will search for future updates time, day, month or year of admission. of this review, were also specified in the protocol for this review. b) Allocation concealment 4. METHODS - REVIEWERS’ CONTRIBUTIONS The protocol stated that we would follow the statistical guidelines Adequate: if participants and investigators enrolling participants in the Cochrane ENT Group Guidelines for Reviewers (Cochra- cannot foresee assignment. Adequate measures include a priori neENTGuideline, updated November 2000), and that two re- numbered or coded containers of identical appearance, central viewers (CM and JA) would independently: randomisation; sequentially numbered, opaque, sealed envelopes; * select trials (at least for electronic searches), review the titles and or other descriptions that contained convincing elements of con- abstracts of articles identified by the search strategy, and assess full cealment. texts for eligibility; Inadequate: trials in which the authors reported an approach that * assess the methodological quality of all trials identified as eligible could not be considered adequate (e.g. methods of allocation such for inclusion (and report the level of agreement between the two as alternation methods or use of case record numbers are not con- reviewers); cealed). * extract data of study characteristics, including methods, partici- pants, interventions and outcomes, and record these on standard Unclear: trials in which the authors either did not report an allo- forms; and cation concealment approach at all or allocation concealment was * enter data onto Review Manager 4.2. stated but method not described.

However, while CM and JA independently reviewed titles and ab- Baseline comparison of experimental groups will confirm whether stracts of articles identified by the search strategy, only CM as- treatment arm allocation appears to be unbiased. sessed the full texts for eligibility and methodological quality, ex- c) Blinding tracted data, and entered data onto Review Manager 4.2. JA and CG provided a second opinion on trials CM had selected for in- Double blind: the trial uses a placebo, or a double dummy tech- clusion; CG reviewed those where there was any ambiguity about nique such that neither the participant or care provider/assessor the methods used, for the methodological quality and data extrac- know which treatment is given. tion; and JA provided further information where this had been Single blind: the participant or care provider/assessor is aware of obtained from authors of trials included in the previous review the treatment given. ’Interventions for chronic suppurative otitis media’ (Acuin 1998). The three authors resolved any disagreements through discussion. Open: all parties are aware of treatment. 5. ASSESSMENT OF METHODOLOGICAL QUALITY d) Inclusion of all randomised participants

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 15 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Adequate: More than 90% of people randomised in the trial were ACKNOWLEDGEMENTS included in the analysis.

Inadequate: Less than 90% of those randomised in to the trial The authors wish to thank Professor Paul Garner of the Cochrane were included in the analysis. Infectious Diseases Group, Liverpool School of Tropical Medicine, Unclear: It is not clear how many people were originally ran- for his advice and support, and Miss Gemma Healy and Carolyn domised into the trial or analysed. Doree of the Cochrane ENT Disorders group for their help with the searches. 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 SOURCES OF SUPPORT media. However, we only did so if the authors reported stratifying randomisation by diagnosis. Where information was not reported External sources of support 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 • Cochrane Ear, Nose and Throat Disorders Group UK been linked to trend). • Department for International Development UK

POTENTIAL CONFLICT OF Internal sources of support INTEREST • Liverpool School of Tropical Medicine UK None known. • Cochrane Infectious Diseases Group UK

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Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 21 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd van Hasselt 1997 References to studies awaiting assessment ∗ van Hasselt P.CBM 1997: Pilot trial of treatment of Chronic Sup- Andersen 2002 purative Otitis Media (CSOM) with several types of ear drops in Andersen JB. Otitis media and antibiotics (7) [Otitis media of an- Nkota Kota District, Malawi. Internal Report of Christian Blind tibiotika]. Ugeskrift for Laeger 2002 (August 12);164(33):3876–7. Mission Int., Bensheim, Germany 1997. Iarlykov 1995 van Hasselt P,van Kregten E. Treatment of chronic suppurative otitis Iarlykov SA, Poliakova SD, Zemskov AM. Correction of immuno- media with ofloxacin in hydroxypropyl methylcellulose ear drops: a logic disorders in patients with chronic suppurative otitis media. Vest- clinical/bacteriological study in a rural area of Malawi. 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Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 23 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd TABLES

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.

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 24 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 25 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.

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 26 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 27 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 28 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 29 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.

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 30 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 31 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).

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 32 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 33 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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 34 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).

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 35 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)

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 36 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).

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 37 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic ADDITIONAL TABLES

Table 01. Methodological quality of included studies

Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up

Browning 1983 Unclear Unclear Unclear Single blind Inadequate Treatment allocation Medication was supplied in Baseline characteristics Allocation was kept blinded 32% dropout: 24/75 described as random, using the clinic by the pharmacist (including the distribution from the clinicians, with participants were defaulters random numbered list kept using the random numbered of participants with and the necessary exception of or non-compliers (i.e. used by the pharmacist, who list, after eligibility without modified radical antiseptic, given by the <75% of the medication). dispensed the medication, assessments by the clinicians, mastoidectomy) not otologist after aural toilet. (Numbers excluded not but method of sequence who were blinded (except reported. given by treatment group or code generation was not for antiseptic). Whether diagnosis). stated. treatment was concealed Results given for the 51 al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally The choice of antibiotic from the pharmacist is not participants who complied

h ie os Ltd Sons, & Wiley ohn depended on sensitivity discussed. with treatment only. 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). s(Review) ns de Miguel 1999 Unclear Unclear Unclear (partly comparable) Unclear Adequate Treatment allocation Allocation concealment not Baseline characteristics not Blinding not mentioned. No withdrawal was reported. described as random, but reported - nor was blinding. reported for each group, 125 participants were randomisation method was except infective organism reported as entered into the not stated. (which was comparable trial and analysed (25 per Did not discuss whether except fewer Pseudomonas group - i.e. 100 for this randomisation was stratified aeruginosa isolated for the review). 38 by the 4 diagnostic groups ciprofloxacin 0.2% group). oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 01. Methodological quality of included studies (Continued )

Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up

(and results not reported The distribution of the 4 separately in trial report). diagnostic groups was not reported.

Esposito 1990 Unclear Unclear Mostly Unclear Adequate Treatment allocation Allocation concealment not Groups comparable at Blinding not mentioned. No withdrawal was reported. described as random, but reported - nor was blinding. baseline for age and sex, 60 participants were randomisation method was but the group receiving reported as entered into the not stated. oral ciprofloxacin only trial and were analysed (20 had a higher prevalence of per group). Pseudomonas and hence lower number of gram- al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally positive cocci. h ie os Ltd Sons, & Wiley ohn Esposito 1992 Unclear Unclear Yes Unclear Adequate Treatment allocation Allocation concealment not Balanced for age and sex. Blinding not mentioned. No withdrawal was reported. described as random, but reported - nor was blinding. No other baseline characters 60 participants were randomisation method was were reported. reported as entered into the not stated. trial and were analysed (30 per group). Mira 1992 Adequate Unclear Yes Single blind Unclear Participants were Allocation concealment Groups comparable at Described as single blind 1/248 (0.4%) participants randomised according to not reported - but trial was baseline for number of but no further information (who received systemic+ blocked randomisation reported to be single blind. participants, age, sex, provided. topical therapy) dropped tables (block size 4), one for diagnosis, presence and out of the study before each centre. severity of symptoms, and completing treatment, bacteriology. and failed to attend the (The slight higher number scheduled visits.

s(Review) ns of tympanoplasty and BUT not reported numbers mastoidectomy participants analysed (for cultures on systemic+topical taken or symptom scores; treatment, was not or standard deviation statistically significant). for symptom scores), to confirm whether adequate numbers were included in

39 the analyses. oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 01. Methodological quality of included studies (Continued )

Study ID Sequence generation Alloc. concealment Balance at baseline? Blinding Follow-up

Papastavros 1989 Inadequate Unclear Mostly but not for morbidity Unclear Adequate Treatment allocation Allocation concealment not Distribution of cases were Blinding not mentioned. No withdrawal was reported. described as random (after reported - nor was blinding. balanced between systemic 90 participants with 119 obtaining culture results), and topical modalities for ears (71 antibiotics, 48 but randomisation method age, sex, socioeconomic antiseptics) were reported as was not stated. class, duration of disease and entered into the trial and Randomisation does not type of chronic otitis (tubo- were analysed. appear to be stratified by the tympanic or atticoantral). different diagnostic groups. But morbidity was higher 6 participants considered at in the systemic antibiotic high risk of complication group, due to non-random

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally were all allocated systemic allocation of 6 complicated treatment for ethical reasons, to this group. h ie os Ltd Sons, & Wiley ohn and not randomised. The distribution of other Choice of antibiotic complications or previous depended on bacterial surgery was not reported. cultures and in vitro sensitivity; Choice of antiseptic was determined at random.

Povedano 1995 Unclear Unclear Yes Unclear Adequate Treatment allocation Allocation concealment not Groups comparable at Blinding not mentioned. All participants were described as random, but reported - nor was blinding. baseline for age, sex and reported to have completed randomisation method was bacteriology. the study, with no dropouts. not stated.

Supiyaphun 2000 Unclear Unclear Yes Investigator blinded Unclear Treatment allocation Allocation concealment Groups comparable at Double dummy for oral 1.25% dropout: 1/80 s(Review) ns described as random, but not mentioned - but baseline for demographic medication - placebo oral participants (participant randomisation method was ’investigator-blinded’ trial. (age, sex) and disease-related capsules for the ofloxacin received topical ofloxacin) not stated. characteristics (laterality of arm, were the same size and missed visits and therefore infection, size, duration, and colour as amoxicillin 500mg excluded from the study. cause of perforation, and capsules. But results were only pathogenic organisms). presented as percentage of ears, not actual numbers or 40 totals; rates reported do not oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic 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 Adequate Mostly Unclear Adequate Participants were Envelopes with treatment Groups comparable at Blinding not mentioned. 7% dropout rate: 4/60 randomised into 2 groups groups were concealed. baseline for perforation participants excluded from by drawing concealed size, mucosal inflammation, the analysis (3/30 oral envelopes. nature of discharge Augmentin, 1/30 topical (more purulent cases ofloxacin).

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally for Augmentin, but not Reasons for exclusion: statistically significant), and 3 defaulted follow-up (2 h ie os Ltd Sons, & Wiley ohn bacteriology (but slightly Augmentin, 1 ofloxacin) lower rate of bacteria isolated 1 did not complete in ofloxacin (62%) than the course of treatment Augmentin (70%)). (Augmentin) due to gastric Ofloxacin had better upset. overall in vitro antibiotic susceptibility results than Augmentin, due to its better activity against Pseudomonas species. s(Review) ns 41 Table 02. Bilateral Disease: Numbers for Ears vs Participants

Handling bilat Study ID # of particpants # of ears % bilateral cases cases Results: pt or ears?

Browning 1983 75 randomised - Not reported Not reported One ear was chosen Participants all treatments; not at random by reported by group. the pharmacist 51 analysed: (method of choice 13 systemic unknown). antibiotics 18 topical antibiotics 20 topical antiseptics 19/51 (37%) were post modified radical mastoidectomy - numbers and results were not presented separately. de Miguel 1999 Total: 125 (25 per Not reported? Not reported? Not reported? Participants? group; i.e. 100 for this review) Esposito 1990 Total: 60 adults Not reported Not reported Unclear - reported Participants (20 per treatment at participant level. group) Esposito 1992 Total: 60 adults Not reported Not reported Unclear - reported Participants (30 per treatment at participant level. group) Mira 1992 Randomised Not reported Not reported Unclear - reported Participants participants: at participant level, 248 all diagnoses: but reported scores (120 systemic without numbers. 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:

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 42 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Table 02. Bilateral Disease: Numbers for Ears vs Participants (Continued )

Handling bilat Study ID # of particpants # of ears % bilateral cases 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 Analysed ears: Total 29/90 Analysed and Ears participants: 119 total (68 (32.2%) (not reported for 90 total (not tubotympanic; 51 reported by group). numbers of ears reported by group). atticoantral): separately. 71 systemic antibiotics: (42 tubotympanic; 29 atticoantral) 48 topical antiseptics: (26 tubotympanic; 22 atticoantral); (21 hydrogen peroxide drops; 27 borax powder). Povedano 1995 Total: 60 adults (30 Not reported - same Not reported Unclear - reported Participants? (For per group). as participants? at participant clinical success). level, although Unclear for bacteriology for ears bacteriology results. matches number of participants? Supiyaphun 2000 80 randomised 89 analysed ears: Analysed rates: Unclear - results % ears but rates do participants: (45 oral amoxicillin Total 10/79 were only presented not equate to whole (40 oral amoxicillin + topical (12.7%) as percentage of ears. + topical chloramphenicol; Oral amoxicillin ears, not actual chloramphenicol; 44 topical + topical numbers or totals; 40 topical ofloxacin ofloxacin). chloramphenicol: but rates reported drops). 5/40 (12.5%) do not equate to 79 analysed Topical ofloxacin whole ears when participants: drops: 5/39 using total numbers (40 oral amoxicillin (12.8%). of ears (sometimes + topical match number of chloramphenicol; participants more 39 topical ofloxacin closely). drops)

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 43 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Table 02. Bilateral Disease: Numbers for Ears vs Participants (Continued )

Handling bilat Study ID # of particpants # of ears % bilateral cases cases Results: pt or ears? Yuen 1994 60 recruited Not reported Not reported Unclear - reported Participants participants: at participant level. (30 oral Augmentin; 30 topical ofloxacin). 56 analysed participants: (27 oral Augmentin; 29 topical ofloxacin).

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 44 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep? Browning 1983 Active chronic 1) Non-otitis Not specified Yes. Not reported 19/51 (i.e. No otitis media Cholesteatoma inclusion - but all Sensitivity of 37%) analysed including 2) Aural polyp criteria: participants isolated aerobic participants previous 1) Over 16 years were secondary flora determined had previously modified radical old referrals. the choice of undergone mastoidectomy Exclusions antibiotic. modified radical participants. - see otitis Participants with mastoidectomy exclusions; no Pseudomonas (not provided other exclusions spp were not by treatment were specified. randomised to group). oral (systemic) al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally antibiotic. h ie os Ltd Sons, & Wiley ohn de Miguel 1999 Otorrhoea Not reported Previous Not specified Indicated. Yes: some a) 45 Simple No diagnosed on antibiotic Unclear whether permanent chronic otitis otoscopy under treatment was required for alterations in media; microscopy - 4 allowed, and had inclusion or not. the mucosa for b) 32 “Osteitic” subgroups: been received diagnostic group chronic otitis a) Simple by 79/125 of b): “Osteitic” media (with chronic otitis all randomised chronic otitis tympanosclerosis media - no participants media. or chronic osteitic changes, (63.2%). granulomatosis); tympanosclerosis Analgesics and c) 17 or antipyretics Cholesteatoma- cholesteatoma; allowed during tous chronic b) Osteitic the study. otitis media; chronic otitis Age ranged from d) 31 Post media - with 6-83 years. surgery cases. s(Review) ns changes to Other eligibility N = 125 (ie the ossicular criteria: all included chain and some None specified. participants), permanent but only 100 alterations in included in the mucosa this review (tympanosclero- (4 treatment 45 sis or chronic groups) - oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

granulomatosis); number per c) treatment not Cholesteatoma- available. tous chronic otitis media; d) Post surgery cases.

Esposito 1990 Mild or 1) Inclusion criteria Not reported Indicated. Not reported None specified n/a moderate Cholesteatoma - other: other than Unclear whether - see otitis

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally chronic 2) Mastoiditis 1) Adults at least ’chronic required for exclusions. suppurative 18 years old suppurative inclusion. h ie os Ltd Sons, & Wiley ohn otitis media in (mean age was otitis media in Bacteria was the acute stage. 38) the acute stage’. isolated for all 2) Informed participants participant before treatment. consent Exclusion criteria - treatment related 1) History of previous allergy to quinolone derivatives No participants took any other drug during the s(Review) ns study. 63% (38/60) had received antibiotic treatment for at least 5 days before study 46 treatment, oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

without significant improvement. Exclusion - other: 1) Pregnant women 2) Younger than 18 years old No participants

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally had any underlying h ie os Ltd Sons, & Wiley ohn diseases (such as diabetes).

Esposito 1992 Mild or 1) Inclusion criteria Otitis media Yes. Not reported None specified n/a moderate Cholesteatoma - other: lasted at least 3 Bacteriological - see otitis chronic 2) Mastoiditis 1) Adults at least years; culture positive exclusions. suppurative 18 years old Purulent for Pseudomonas otitis media in (range was 18- otorrhoea susceptible the acute stage, 65, mean 39) recurrent at least to in vitro with 2) Informed once annually; ciprofloxacin perforation of participant and and gentamicin the tympanic consent Resistant required for membrane, and Exclusion criteria episodes of study inclusion. bacteriological - treatment purulent culture positive related: otorrhoea had s(Review) ns for Pseudomonas 1) History been constant susceptible of allergy to for at least 15 to in vitro quinolones or days. ciprofloxacin aminoglycosides and gentamicin. No participants Diagnosis took any other according to drug during the 47 the following study. oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

criteria: 67% (40/60) had 1) Otitis media received previous had lasted at antibiotic least three years treatment for 2) Purulent 5-10 days; otorrhoea had interrupted 1- recurred at least 7 days before once annually study entry, after 3) Resistant no significant episodes of improvement.

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally purulent Exclusion otorrhoea had criteria - other: h ie os Ltd Sons, & Wiley ohn been constant 1) Pregnant for at least 15 women days. 2) Younger than 18 years No participants had any underlying diseases (such as diabetes)

Mira 1992 Suppuration 1) Otitis externa Inclusion criteria Not specified Indicated. Oedema severity a) 196 recurrent No following: 2) - other: Not required scores included simple CSOM a) recurrence Cholesteatoma 1) Age over 14 for inclusion as an outcome. (99 systemic; (new acute years (mean - causative 97 systemic+ phase) of simple (SD) was 42.6 organism topical) s(Review) ns CSOM (13.7); range 14- only isolated b) 26 b) 79). in 145/248 suppuration tympanoplasty 2) Informed (58.5%) following c) consent. participants at tympanoplasty mastoidectomy Exclusion criteria baseline. (10 systemic; - treatment Eradication of 16 systemic+ related: isolated bacteria topical). 48 1) Ascertained reported (also by c) 26 oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

or suspected pathogen) as an suppuration hypersensitivity outcome. following to mastoidectomy cephalosporins (11 systemic; and/or 15 systemic+ penicillins topical). No other antibiotics were allowed throughout the

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally study period, but appropriate h ie os Ltd Sons, & Wiley ohn drugs for concomitant diseases were permitted. Exclusion criteria - other: 1) Concomitant serious diseases (neoplasia, renal or hepatic insufficiency) 2) Known or suspected pregnancy or

s(Review) ns lactating.

Papastavros Participants with 1) Non- Inclusion criteria Range 6 Indicated. Included in a) 68 persistent Only for 1989 discharging ears. suppurative cases - treatment months (shortest Clinical response definition tubo-tympanic tubotympanic A case of CSOM 2) Cases of related: duration presented by of clinical mucositis: vs atticoantral must meet questionable 1) All existing accepted) to 40 pathogen, and response (colour, 42 systemic disease. either: chronicity medications were years. bacteriological oedema and antibiotics, 1) Persistent discontinued response granulations/ 26 topical 49 drainage for at at least 3 days reported. polyps). antiseptics; oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

least the previous before drainage Not reported (37 had 6 months; or for cultures and as an inclusion simple chronic 2) Drainage at 5 days before criterion. mucositis 1st visit and randomisation confirmed on history of at least and starting surgery). 3 recurrences study treatment b) 51 atticoantral during the (started after disease: previous 12 results of culture 29 systemic months. were available). antibiotics, Classified as: Inclusion criteria 22 topical

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally a) persistent - other antiseptics; tubo-tympanic 1) Written (28 had h ie os Ltd Sons, & Wiley ohn mucositis informed cholesteatoma (simple chronic consent and/or osteitis mucositis) Age range was confirmed b) atticoantral 11-79 years, on surgery - disease median 49. cholesteatoma (cholesteatoma All participants was undiagnosed and/or osteitis) were white, from pre-operatively (Diagnosed rural areas or in 2 cases). on clinical a large urban Other findings: examination; centre. Around one later confirmed third of cases on surgery for 65 had 1 or more who underwent of: otalgia, surgery). headache, Other findings tinnitus, s(Review) ns were: recurrent Symptoms true vertigo, including dizziness and/or otalgia, a sensation of headache, imbalance. tinnitus, About one sixth recurrent of cases had a 50 true vertigo, positive fistula oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

dizziness and/or sign. a sensation of 4 participants imbalance. had previously Positive undergone a fistula sign mastoidectomy. demonstrable 6 high risk after removing complicated discharge or cases were debris. allocated Previously systemic

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally undergone antibiotics. mastoidectomy. h ie os Ltd Sons, & Wiley ohn Cases at high risk of complication, allocated systemic antibiotics (not randomised).

Povedano 1995 Chronic Not reported Inclusion criteria Not specified Yes. Not reported None specified n/a otorrhoea in the - other: Indicated active phase. 1) Written pre-and post informed treatment consent bacteriology, 2) Adults (age and reported range was 18-65 as an outcome years) measure. s(Review) ns Exclusion criteria All cases had - treatment bacteria isolated related: before treatment, 1) Previous or but not specified concurrent use as an inclusion of any treatment criteria. 2) Previous or 51 suspected allergy oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep?

to quinolones Exclusion criteria - other: 1) Under 18 years old 2) Underlying diseases, eg diabetes, cardiopathy, etc.

Supiyaphun Active chronic 1) Inclusion criteria >21 days Indicated. Assessed on None specified n/a al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally 2000 otitis media Cholesteatoma - other: duration Baseline microscopy at

h ie os Ltd Sons, & Wiley ohn with purulent or or large aural 1) Over 15 years (perforation) bacteria and baseline. mucopurulent polyp in the old (range was bacteriological Improvement otorrhoea, middle ear or 15-78, mean outcome in severity and and central mastoid (SD) 33 (12.5)) reported but disappearance perforation of 2) History of ear Exclusion criteria not required for of middle ear the tympanic surgery within - treatment inclusion. inflammation membrane of the previous year related: 10.1% reported as an greater than 21 1) Therapy participants outcome. days duration. with systemic (9/89; 9.1% antibiotics or ofloxacin, 11.1% any ototopical amoxicillin+ agents within 2 chlorampheni- weeks col) had no 2) Allergy to growth; 9 penicillin, chlo- further cases

s(Review) ns ramphenicol, (10.1%) had or quinolone contamination. antibiotics Exclusion criteria - other: 1) Pregnant or lactating. 52 Yuen 1994 Active chronic 1) Inclusion criteria Not specified Indicated. Severity of None specified n/a oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 03. Participant eligibility criteria, including CSOM diagnostic criteria (Continued )

CSOM Otitis Other elig Disease Mucosal Other Other diags: Study ID diagnosis exclusions criteria duration Bacteriology? appearance? diagnoses? sep? suppurative Cholesteatoma - other - but acute Not required for middle ear otitis media 2) Discharging 1) Adults (range otitis media was inclusion. mucosal with central mastoid cavity was 18-70 years, an exclusion Baseline inflammation perforation. 3) Large aural median 35) criterion. bacteriology was reported at polyp All participants reported: baseline and as 4) Acute had no prior Only 37/56 an outcome. traumatic antibiotic (66%) of perforation treatment participants 5) Acute otitis for at least 1 had pathogens media week before found in baseline 6) Presence of a commencing cultures (62% al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally grommet study treatment. ofloxacin, 70%

h ie os Ltd Sons, & Wiley ohn 7) History of Exclusion Augmentin). radiotherapy of criteria - other: the temporal None specified. bone 8) Otomycosis s(Review) ns 53 oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic 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- 1) Systemic antibiotics: 1) Systemic antibiotics: All treatments: 4 weeks All groups: Not reported. quinolone antibiotic: oral (formulation not 1-2g/day (self-treat) Weekly aural toilet oral cephalexin, specified). 3) Antiseptic: once by otologist, using flucloxacillin, 3) Topical antiseptics: weekly (insufflation microscopic vision cloxacillin or insufflation of after aural toilet, by and suction aspiration amoxicillin (self- antiseptic powder. otologist) (dose not when necessary. treated). reported). 3) Topical antiseptics:

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally insufflation of boric acid and iodine powder h ie os Ltd Sons, & Wiley ohn 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.

Systemic quinolone & non-quinolone antibiotics vs topical antiseptic s(Review) ns Papastavros 1989 1) Systemic antibiotics 1) Systemic antibiotics: 1) Systemic antibiotics: Mean duration: (overall Both groups (all All existing medications - choice of: a) intravenous; various doses, 2-3 times 20.5 days) treatments): were discontinued a) Intravenous non- b-d) oral daily. 1) Systemic antibiotics: Toileting and at least 3 days quinolones: piperacillin 2) Topical antiseptics: a) Intravenous non- 21.4 days debridement of the before drainage for (2), aztreonam a) Hydrogen peroxide: quinolones: piperacillin (19.4 tubotympanic; ear with suction as cultures and 5 days (Azactam) (12); instillation of drops 1000mg twice daily; 24.3 atticoantral) necessary, performed at before randomisation b) Oral non- b) Borax: insufflation Azactam 500mg 3 2) Topical antiseptics: regular visits. and starting study 54 quinolones: amoxicillin of powder. times daily; 19.2 days treatment (started after oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 04. Intervention regimens used (Continued )

Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds

+ clavulanate (2), b & d) Oral non- (19.7 tubotympanic; results of culture were erythromicin (2), quinolones: 18.7 atticoantral) available). metronidazole (6), Twice daily: Duration up to 2- sulfamethoxazole + erythromycin 1000mg; 3 weeks: planned trimethoprim (29); sulfamethoxazole to continue for 10 c) Oral quinolones: 800mg + trimethoprim days before deemed ciprofloxacin (8); 160mg unsuccessful, or 10 d) Oral quinolone+ 3 times daily: additional days after non-quinolones: amoxicillin+clavulanate successful outcome. ciprofloxacin + 625mg; metronidazole Unsuccessful cases were metronidazole (10); 500mg; transferred to the other

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally Choice of antibiotic c & d) Oral quinolone: treatment group or depended on culture ciprofloxacin 500mg released from the study. h ie os Ltd Sons, & Wiley ohn and sensitivities twice daily. 6 participants at high 2) Antiseptics - not risk of complications reported. 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 s(Review) ns clinical response and culture taken every c10 days. Crossover: failures on initial treatment were transferred to the alternative group as 55 new cases (numbers oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic 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: 1) Systemic antibiotics: 1) Systemic antibiotics: All treatments: All groups: Not reported oral cephalexin, oral (formulation not 1-2g/day (not reported 4 weeks Weekly aural toilet flucloxacillin, specified) by antibiotic) by otologist, using

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally cloxacillin or 2) Topical antibiotics: 2) Topical antibiotics: microscopic vision amoxicillin. eardrops a) Chloramphenicol: and suction aspiration h ie os Ltd Sons, & Wiley ohn 2) Topical antibiotic: 1 or 2 drops, 3 times when necessary. Chloramphenicol daily; (Chloromycetin), or b) gentamicin: 3 or 4 gentamicin (Genticin) drops, 4 times daily. 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. s(Review) ns Systemic non-quinolone vs topical quinolone Esposito 1992 1) Systemic 1) Systemic 1) Systemic non- All treatment: 5-10 Not specified No participants non-quinolone: non-quinolone: quinolone: 80mg days (5 days initially; took any other drug intramuscular intramuscular twice daily (according if no cure after 5 days, during the study. 67% gentamicin sulfate injectable vials 2) to the manufacture’s continued until cure (40/60) had received (gentamicin injectable Topical quinolone: dosing suggestions) but not longer than 10 previous antibiotic 56 vials provided by eardrop solution 2) Topical quinolone: days total). treatment for 5-10 oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 04. Intervention regimens used (Continued )

Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds

Schering Plough, 250 micrograms/mL; 4 days; interrupted 1-7 Milan, Italy) 2) drops twice daily days before study entry Topical quinolone: after no significant ciprofloxacin improvement. hydrochloride in saline solution (ciprofloxacin powder provided by Bayer Italia Spa, Milan, Italy) Yuen 1994 1) Systemic non- 1) Systemic: oral 1) Systemic: 375mg Both treatments: Both groups: All participants had quinolone: oral Augmentin Augmentin 1 week Suction cleaning before no prior antibiotic

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally amoxicillin-clavulanic 2) Topical ofloxacin 2) Topical: 0.3% 1st dose treatment for at least 1 acid (Augmentin) eardrops ofloxacin week before starting h ie os Ltd Sons, & Wiley ohn 2) Topical quinolone: Both treatments: 3 study treatment. ofloxacin eardrops times daily

Systemic quinolone vs topical quinolone De Miguel 1999 1) Systemic: oral 1) Systemic oral tablet 1) Systemic: 500mg All treatments: All groups: Analgesics and ciprofloxacin 3) & 4) Topical eardrop twice daily (1 tablet 7 days Aspiration before antipyretics allowed 3) Topical: solution every 12 hours) starting treatment only. during the study. ciprofloxacin 0.2% 3) & 4) Topical 0.2% 63.2% (79/125) 4) Topical: & 0.5% ciprofloxacin: of all randomised ciprofloxacin 0.5% 3 drops 3 times daily participants had (c0.15mL every 8 received previous hours) antibiotic treatment. Esposito 1990 1) Systemic: oral 1) Systemic oral tablet 1) Systemic: 250mg All treatments: Not specified No participants took ciprofloxacin 3) Topical eardrop twice daily 5-10 days (5 days any other drug during

s(Review) ns 3) Topical: solution 3) Topical: 250 initially; if no cure after the study. ciprofloxacin in saline micrograms/mL, 3 5 days, continued until 63% (38/60) had solution drops twice daily cure but not longer received antibiotic than 10 days total). treatment for at least 5 days before study treatment, without significant

57 improvement. oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 04. Intervention regimens used (Continued )

Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds Povedano 1995 1) Systemic: oral 1) Systemic oral 1) Systemic: 500mg Both treatments: Not specified No previous or ciprofloxacin (tablet?) twice daily (every 12 10 days concurrent use of 2) Topical: 2) Topical eardrop hours) any treatment was ciprofloxacin in saline solution 2) Topical: 250 allowed (reported as an solution microgram/mL (0.9%); exclusion criterion); 5 drops twice daily washout period not (every 12 hours) reported.

Systemic antibiotic alone vs systemic + topical antibiotic Systemic non-quinolone vs systemic + topical non-quinolone Mira 1992 1) Systemic antibiotic + Both groups: Systemic: Both treatments: Both groups: No other antibiotic

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally topical placebo: Systemic: 1) & 2): 2 g daily (1 7 days Aspiration of local treatments were intramuscular intramuscular vial containing 1g secretions by specialist allowed throughout h ie os Ltd Sons, & Wiley ohn ceftizoxime + topical Topical: eardrops Ceftizoxime every 12 before 1st dose only. the study period, but normal saline solution hours). appropriate drugs for 2) Systemic + topical Topical: concomitant diseases antibiotic: 1) 4 ml normal saline were permitted. intramuscular solution ceftizoxime + topical 2) 2g ceftizoxime in ceftizoxime in saline 4ml saline solution solution Topical - both groups: All treatments: 4ml twice daily (2ml Initial treatment by initially, using a specialist in the clinic; gradated syringe; the thereafter by a relative remaining 2ml 3-5 of the participant minutes later). following instruction. Ear gauze applied after Ceftizoxime vials each dose (for 8hrs s(Review) ns (intramuscular): after initial application; Eposerin R, Farmitalia. then, 2 hours after morning doses, and overnight for evening doses).

Systemic quinolone vs systemic + topical quinolone 58 De Miguel 1999 1) Systemic: oral 1) Systemic oral tablet 1) & 2) Systemic: All treatments: 7 days All groups: Aspiration Analgesics and oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 04. Intervention regimens used (Continued )

Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds

ciprofloxacin 2) Systemic oral tablet 500mg twice daily (1 before starting antipyretics allowed 2) Systemic + topical: + topical eardrops tablet every 12 hours) treatment only. during the study. oral ciprofloxacin + 2) Topical: 0.2% 63.2% (79/125) topical ciprofloxacin ciprofloxacin, 3 drops 3 of all randomised 0.2% times daily (c0.15mL participants had every 8 hours) received previous antibiotic treatment.

Esposito 1990 1) Systemic: oral 1) Systemic oral tablet 1) & 2) Systemic: All treatment: 5-10 Not specified No participants ciprofloxacin 2) Systemic oral tablet 250mg twice daily days (5 days initially; took any other drug 2) Systemic + topical: + topical eardrop 2) Topical: 250 if no cure after 5 days, during the study. 63% oral ciprofloxacin + solution micrograms/mL, 3 continued until cure (38/60) had received al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally ciprofloxacin in saline drops twice daily but not longer than 10 antibiotic treatment

h ie os Ltd Sons, & Wiley ohn solution days total). 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 Systemic (both groups): 1) Oral amoxicillin Both treatments: Both groups: No therapy with non-quinolones: oral oral capsules 500mg + topical 1% 2 weeks Performed on Day 0 systemic antibiotics or amoxicillin + topical Topical (both groups): chloramphenicol 3 only. any ototopical agents chloramphenicol. eardrops/otic solution drops; both 3 times within 2 weeks was 2) Systemic placebo daily allowed. + topical quinolone: 2) Oral placebo 3 times oral placebo + topical daily + topical 0.3% ofloxacin ofloxacin 6 drops twice s(Review) ns daily

Systemic + topical quinolone vs topical quinolone De Miguel 1999 2) Systemic + topical: 2) Systemic oral tablet 2) Systemic: 500mg All treatments: 7 days All groups: Aspiration Analgesics and oral ciprofloxacin + + topical eardrop twice daily (1 tablet before starting antipyretics allowed topical ciprofloxacin solution every 12 hours) treatment only. during the study. 0.2% solution 3) & 4) Topical eardrop All groups: topical: 63.2% (79/125) 59 3) Topical: solution 0.2% (groups 2 & 3) of all randomised oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 04. Intervention regimens used (Continued )

Study ID Intervention Formulation & route Dose/strength & freq Duration Ear Toilet Concurrent meds ciprofloxacin 0.2% & 0.5% (group 4): participants had 4) Topical: 3 drops 3 times daily received previous ciprofloxacin 0.5% (c0.15mL every 8 antibiotic treatment. hours) Esposito 1990 2) Systemic + topical: 2) Systemic oral tablet 2) Systemic: 250 mg All treatments: Not specified No participants took oral ciprofloxacin + + topical eardrop twice daily 5-10 days (5 days any other drug during ciprofloxacin in saline solution 2) & 3) Topical: 250 initially; if no cure after the study. solution 3) Topical eardrop micrograms/mL, 3 5 days, continued until 63% (38/60) had 3) Topical: solution drops twice daily cure but not longer received antibiotic ciprofloxacin in saline than 10 days total). treatment for at solution least 5 days before

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally study treatment, without significant h ie os Ltd Sons, & Wiley ohn improvement. s(Review) ns 60 oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

Browning 1) Participants Participant 1983 with active, mucoid or inactive ears after 4 weeks of treatment.

de Miguel 1) Clinical ** 1) Hearing 1) Evidence 1) Bacteriology Negative Participant? 1999 microbiologi- assessment of ototoxicity assessed and bacterial cal cure - not - pure tone on hearing reported: culture specified how audiometry. assessment a) post- appears to be al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally defined or Only reported (measured treatment included in the

h ie os Ltd Sons, & Wiley ohn assessed. negative by pure tone bacteria definition of Assessed at findings in audiometry) isolated for cure. days 1, 8 (end relation to - reported treatment of treatment) ototoxicity negative failure cases. and 15. - see safety statement only. b) pre- and Unclear if column. ** 2) Adverse post-treatment reported events bacteria results are for reported. in vitro day 8 or 15. sensitivity.

Esposito 1990 1) Clinical 1) All ** 1) Hearing 1) Side effects: 1) Participants Participant response: participants assessment ’accurate Bacteriological were participants who were - pure tone inquiry’ at outcome: clinically and with cure clinically and audiometry each clinical 1a) bacteriology (dry ears), bacteriolog- and vestibular control (every Participants assessed every improvement, ically cured tests. 2-3 days). with negative 2-3 days; s(Review) ns or failure. 24 hours after Measured 2) Ototoxicity: aerobic evaluation Improvement 5-10 days before and audiometric cultures stated 24 hours has been treatment 24 hours post measurement (reported and 14 days grouped with confirmed treatment. and vestibular eradication, post 5-10 days failure for this their clinical Only assessed tests for persistence, treatment. review. status 14 for groups treatment and super- Stated response days post- receiving groups 2 and infection). 61 24 hours and treatment. topical 3 (receiving 1b) oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

14 days after ciprofloxacin. topical Responsible 5-10 days Only reported ciprofloxacin) bacteria pre treatment. negative - before and and post The results findings in 24 hours after treatment. reported relation to 5-10 days 1c) appear to be ototoxicity therapy. Ciprofloxacin for 24 hours - see safety resistance post-treatment column. ** (none (i.e. day 6-11); detected). all those cured Bacteriology

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally confirmed assessed every their status 2 2-3 days; h ie os Ltd Sons, & Wiley ohn weeks later. evaluation stated 24 hours and 14 days post treatment; reported 24hr results.

Esposito 1992 1) Clinical 1) All ** 1) Hearing 1) Side effects: 1) Participants Participant response on participants assessment - “thorough Bacteriological were otoscopy: who were audiometry inquiry” at outcome: clinically and participants clinically and and vestibular each clinical 1a) bacteriology with cure bacteriolog- tests (all examination Participants assessed every (dry ears), ically cured participants). (every 2-3 with negative 2-3 days; improvement, 12 hours after Measured days). aerobic evaluation or failure. 5-10 days before and 2) Ototoxicity: cultures stated 12 s(Review) ns Improvement treatment, 24 hours post audiometric (reported hours, and 14 has been confirmed treatment. measurement eradication or and 21 days grouped with their clinical Only reported and vestibular persistence). post 5-10 days failure for this status 14 and negative tests for all 1b) Sensitivity treatment. review. 21 days post findings in participants, of 12hr post- Stated response treatment; no relation to before and treatment 12 hours, relapses were ototoxicity 24 hours post cultures to 62 14 days and observed. - see safety treatment. ciprofloxacin oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

21 days after column. ** and interrupting gentamicin 5-10 days (no resistance treatment. detected). The results Bacteriology reported assessed every appear to be 2-3 days; for 12 hours evaluation post-treatment stated 12 hours (i.e. after 5- and 14 and

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally 10 days); all 21 days post those cured treatment; h ie os Ltd Sons, & Wiley ohn confirmed reported 12hr their status 2 results. and 3 weeks later.

Mira 1992 ** 1) Clinical 1) Safety: all 1) Eradication Participants Participant (+ course of undesirable of isolated were assessed overall scores disease: events reported bacteria - at days 0 per group) recovered, by the reported (baseline), 3 improved, participant or numbers (for symptoms unchanged or observed by cultured by and otoscopy worsened. the physician pathogen only), 7 (end Scale assessed throughout the at baseline of treatment) according to study period. (T0), end of and 21. absence or treatment (T7) s(Review) ns degree of: and 2 weeks Fever, later (T21). symptoms of infection, negativisation of culture. Results were 63 not reported. oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

** ** 2) Symptom severity scores (3 point scale) for otalgia, otorrhoea (quantity), oedema, and congestion. Assessed and

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally reported scores at days 0, h ie os Ltd Sons, & Wiley ohn 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 Clinical ** 1) Systemic 1) Bacteriology Mucosal Ears 1989 response: adverse - assessed appearance s(Review) ns Assessed effects and before and other as cure, appearance of treatment disease recurrence, complications (days -2 and related factors improvement, or bothersome 0), and every included stagnation and allergic 10 days; in clinical aggravation. reactions 1a) outcome Reported cure, (assessed Bacteriological assessment. 64 improvement, by close response oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

or failure. monitoring by (aerobic and Assessed independent anaerobic) according to team of Classed as (criteria for internists) - eradication cure): results were (at least 2 1) Discharge: not reported. consecutive presence, ** sterile cultures degree, at least 10 days turbidity/ apart); relapse; colour and persistence;

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally odour (absent) new 2) Mucosal infection; or h ie os Ltd Sons, & Wiley ohn appearance colonization. (light pink) Reported 3) Mucosal eradication & oedema colonisation, granulations or persistence or polyps (absent) recurrence. 4) Reduction/ Also reported disappearance clinical or new response appearance by initial of associated pathogen. symptoms, not Unclear attributable to whether adverse effect reported of treatment: results are for s(Review) ns pain, otalgia, after 10 days tenderness or 2-3 weeks over mastoid, treatment: local sensation ** 1b) Bacteria of pressure, sensitivities tinnitus, (aerobic only) headache, - results not 65 imbalance, reported. ** oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

vertigo, fever, stiff neck. Antibiotic cure rates varied between 0% (erythromycin & piperacillin) to 90% (ciprofloxacin + metronida-

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally zole). Reported h ie os Ltd Sons, & Wiley ohn results for atticoantral and tubotympanic disease separately. Unclear if results reported are for after 10 days or 2-3 weeks treatment.

Povedano 1) Clinical 1) Participant? s(Review) ns 1995 success after Bacteriological 10 days success: treatment: negative cure, cultures or improvement, persistent failure. bacteria. Improvement Assessed 66 has been before and oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

grouped with after 10 days failure, for this treatment. review. Results seem to also relate to ears, but N matches participant numbers (30 per group).

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally Supiyaphun 1) Cure rate - 1) Hearing 1) Side effects 1) Participants % ears - but 2000 disappearance assessments: (recorded at Improvement were seen and rates do not h ie os Ltd Sons, & Wiley ohn of clinical Assessed and each visit). in severity assessed on equate to signs and reported pre- 2) Ototoxicity: scores of Day 0, 7 and whole ears symptoms by and post- pre- and post- clinical signs 14. Day 14: otalgia treatment treatment and symptoms Results were (assessed by audiometric audiometric by Day reported for participant); evaluation (i.e. evaluation 14: otalgia day 14. otorrhoea (i.e. Days 0 and 14) assessed by (assessed by Results were dry ear), and - assessed by an authorised participant); reported as middle ear an authorised audiologist: otorrhoea and percentage of inflammation audiologist for 2a) Bone middle ear ears, not actual (both ototoxicity conduction. inflammation numbers or assessed on monitoring: 2b) Speech (both on totals; but microscopy by 1a) Bone reception microscopy rates reported investigator). conduction. threshold. by the do not equate Dry ear has 1b) Speech 2c) ’Ototoxic investigator). to whole ears s(Review) ns been taken for reception rate’: 2) Pre- when using this outcome. threshold percentage of treatment bac- total numbers Results were 1c) ’Ototoxic ears in which teriology and of ears reported for rate’: the bone susceptibility (sometimes day 14. percentage of conduction of isolates to match number ears in which or speech ofloxacin, of participants the bone reception amoxicillin more closely). 67 conduction threshold were and chloram- oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears?

and/or speech elevated by phenicol. reception >5dB or a 3) Drug threshold were high frequency compliance elevated by hearing loss - scored >5dB or a was detected according to high frequency (with or number of hearing loss without forgotten doses was detected tinnitus). within the (with or previous seven without days - good

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally tinnitus). compliance (0- 3 missed doses) h ie os Ltd Sons, & Wiley ohn was noted by >90% of participants in both groups.

Yuen 1994 1) Participants ** 1) Size of ** 1) Hearing 1) Sign ** 1) Degree of All outcomes Participant with perforation level - of allergic severity (mild, assessed before completely dry (<25%, 25 pure tone reaction moderate, treatment and ear - reported -75%, or audiogram. documented or severe) of weekly for 2 numbers at >75%). Only reported by the authors. symptoms weeks (end of week 2. Reported summary of otalgia, treatment, and baseline results statement, tinnitus, 1 week later). only ** for absence hearing loss, of significant dizziness change in bone and aural s(Review) ns conduction discharge. thresholds at Documented frequencies on card daily 0.5-4kHz. ** by participant - results not reported ** ** 2) Middle 68 ear mucosal oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 05. Outcomes assessed (Continued )

CSOM Time to Time to Hearing Other Participant or Study ID Resolution Healing resolution reappearance improvement Safety outcomes? Other notes ears? inflammation (mild, moderate, or severe). Documented by authors at each visit; reported baseline results only ** ** 3) Nature

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally of discharge (watery, h ie os Ltd Sons, & Wiley ohn mucoid, or purulent). Documented by authors at each visit; reported baseline results only ** s(Review) ns 69 oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 06. Safety

Study ID Treatment comparison Allergic reaction Ototoxicity AE caused withdrawal Other AE

de Miguel 1999 1) Systemic quinolone: oral There was no evidence Other adverse events: 500mg ciprofloxacin. of ’cochleovestibular’ 1) Oral ciprofloxacin: 8 2) Systemic + topical dysfunction during or after gastralgia quinolone: oral 500mg + treatment for any of the 2) Oral + topical cipro 0.2%: topical 0.2% ciprofloxacin. treatment arms. 5 gastralgia; 1 otomycosis 3) Topical quinolone: 0.2% There were no cases of 3) Topical cipro 0.2%: 2 ciprofloxacin. ototoxicity on audiometry otomycosis 4) Topical quinolone: 0.5% carried out after treatment. 4) Topical cipro 0.5%: 4 ciprofloxacin. otomycosis (N = 25 per group) Esposito 1990 1) Systemic quinolone: oral No worsening of audiometric No side effected was

al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally ciprofloxacin, 250mg. and vestibular function recorded in any participant. 2) Systemic + topical related to local therapy was h ie os Ltd Sons, & Wiley ohn quinolone: oral ciprofloxacin observed (only assessed in 250mg + ciprofloxacin participants who received eardrops 250mg/mL. topical ciprofloxacin). 3) Topical quinolone eardrops: ciprofloxacin 250mg/mL. (N = 20 per group) Esposito 1992 1) Systemic non-quinolone: No worsening of the No side effect was recorded intramuscular gentamicin audiometric function after for any participant. sulphate, 80mg. local or parenteral therapy 2) Topical quinolone: was observed. ciprofloxacin hydrochloride eardrops, 250 microgram/ml. s(Review) ns (N = 30 per group) Mira 1992 1) Systemic non-quinolone: “All undesirable effects intramuscular ceftizoxime + resulted from the systemic topical saline solution (N = treatment”: 120). 1) Systemic ceftizoxime 2) Systemic + topical non- only: quinolone: intramuscular + Any event: 2 participants 70 topical ceftizoxime (N=127). (1.67%): oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic 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 A considerable deterioration 1) Systemic+topical non- non-quinolones: oral was observed in bone quinolones: amoxicillin 500mg + topical conduction (P = 1 tinnitus (disappeared after chloramphenicol 0.1% (N= 0.007) in amoxicillin + discontinuing eardrops); 40 participants, 45 ears). chloramphenicol treated 37% treated ears had mild al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally 2) Topical quinolone: oral ears. to moderate soreness from

h ie os Ltd Sons, & Wiley ohn placebo + topical ofloxacin Meanwhile, ofloxacin treated eardrops; 0.3% (N=39 participants, ears improved instead. 2 fungal superimposition 44 ears). The ototoxic rate (percentage (both resolved after specific of ears in which the elevation treatment). of bone conduction or 2) Topical quinolone: speech reception threshold 2 cases of soreness from was greater than 5dB or had eardrops (5.1%); a high frequency hearing 1 fungal superimposition loss, with or without (resolved after specific tinnitus) was significantly treatment). higher in amoxicillin+ chloramphenicol treated ears than in ofloxacin treated ears (p <0.001 for BC and p= 0.03 for SRT) s(Review) ns Yuen 1994 1) Systemic non-quinolone: There was no There were no significant 1) Oral Augmentin: 1) Oral Augmentin: oral Augmentin 375mg. hypersensitivity reaction to differences between the 1 participant did not 1 participant did not 2) Topical quinolone: the topical ofloxacin. pre-treatment and post- complete the course because complete the course because ofloxacin 0.3% eardrops. treatment pure-tone of gastric upset - this of gastric upset - this audiograms of bone participant was excluded participant was excluded conduction thresholds at from the analysis. from the analysis. frequencies of 0.5, 1, 2 and 2) Topical ofloxacin: 71 4 kHz. no participants complained oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The 2006 chroni © for Copyright treatments topical versus antibiotics Systemic Table 06. Safety (Continued )

Study ID Treatment comparison Allergic reaction Ototoxicity AE caused withdrawal Other AE of adverse side effects. al icagn aswt neligerrmperforatio eardrum underlying with ears discharging cally h ie os Ltd Sons, & Wiley ohn s(Review) ns 72 Table 07. Supiyaphun 2000 hearing analysis: pre- and post-treatment audiometry (2 weeks)

Ofloxacin pre Ofloxacin post Ofloxacin p- Amox+CRP pre Amox+CRP Amox+CRP p- Assessment trtmt trtmt value trtmt post-trtmt value

Bone 23.4 +/-9.7 21.2 +/-8.5 p<0.001 22.8 +/-10.4 24.8 +/-10.4 p=0.007 conduction (BC) (dB +/- SD) P-value from paired t test Speech reception 44.6 +/-15.8 41.2 +/-16.6 p=0.002 40.6 +/-18.1 40.9 +/-11.7 p=0.81 threshold (SRT) (dB +/- SD) P-value from chi squared test.

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

ANALYSES

Comparison 01. Systemic antibiotic vs topical antiseptic

No. of No. of Outcome title studies participants Statistical method Effect size 01 Treatment failure (persistent 2 152 Relative Risk (Fixed) 95% CI 0.81 [0.61, 1.08] discharge) at 2-4 weeks

Comparison 02. Systemic antibiotic versus topical antibiotic

No. of No. of Outcome title studies participants Statistical method Effect size 01 Treatement failure (persistent Relative Risk (Fixed) 95% CI Subtotals only discharge)

Comparison 03. Systemic antibiotic vs systemic + topical antibiotic

No. of No. of Outcome title studies participants Statistical method Effect size 01 Systemic quinolone vs systemic 2 90 Relative Risk (Fixed) 95% CI 2.75 [1.38, 5.46] + topical quinolone

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 73 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Comparison 04. Systemic + topical antibiotic vs topical antibiotic

No. of No. of Outcome title studies participants Statistical method Effect size 01 Systemic+topical non- Relative Risk (Fixed) 95% CI Subtotals only quinolone vs topical quinolone 02 Treatment failure (persistent Relative Risk (Fixed) 95% CI Subtotals only discharge)

INDEX TERMS

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

COVER SHEET

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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 74 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Date of most recent 15 November 2005 SUBSTANTIVE amendment What’s New Information not supplied by author

Date new studies sought but Information not supplied by author none found

Date new studies found but not Information not supplied by author yet included/excluded

Date new studies found and Information not supplied by author included/excluded

Date authors’ conclusions Information not supplied by author section amended Contact address Ms Carolyn Macfadyen Research Associate International Health Research Group Liverpool School of Tropical Medicine Pembroke Place Liverpool L3 5QA UK E-mail: [email protected] ; [email protected] Tel: +44 0 7946 620371 Fax: +44 151 705 3364 DOI 10.1002/14651858.CD005608 Cochrane Library number CD005608

Editorial group Cochrane Ear, Nose and Throat Disorders Group Editorial group code HM-ENT

GRAPHS AND OTHER TABLES 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 Systemicantibiotic Topicalantiseptic RelativeRisk(Fixed) Weight RelativeRisk(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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 75 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 Systemicantibiotic Topicalantibiotic RelativeRisk(Fixed) Weight RelativeRisk(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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 76 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 Systemicquinolone Systemc+topicalquin RelativeRisk(Fixed) Weight RelativeRisk(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+topnon-quin Topicalquinolone RelativeRisk(Fixed) Weight RelativeRisk(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 ... )

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 77 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study Systemc+topnon-quin Topicalquinolone RelativeRisk(Fixed) Weight RelativeRisk(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+topicalAb Topicalantibiotic RelativeRisk(Fixed) Weight RelativeRisk(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

Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations (Review) 78 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd