systematic review and meta-analysis
Article in Clinical otolaryngology: official journal of ENT-UK; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery · August 2023
DOI: 10.1111/coa.14084
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M E T A - A N A L Y S I S
Antibiotics versus non-antibiotic treatments for acute otitis externa: A systematic review and meta-analysis
Rosalind Di Traglia
1,2| Ben Tudor-Green
3| Jameel Muzaffar
4| Daniele Borsetto
2| Matthew E. Smith
1,21School of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
2Cambridge Ear Institute, Cambridge, UK
3Department of Otolaryngology-Head and Neck Surgery, University Hospitals Plymouth NHS Trust, Plymouth, UK
4Department of Otolaryngology, Queen Elizabeth Hospital Birmingham, Birmingham, UK
Correspondence
Rosalind Di Traglia, Department of ENT, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0SP, UK.
Email:[email protected]
Funding information Circius Pharma AB
Abstract
Background:
Otitis externa is a condition causing inflammation of the outer ear canal, which presents with itching, discharge and pain. Most cases of acute otitis externa are caused by bacterial infection and are thus treated with antibiotics.
This systematic review and meta-analysis of randomised controlled trials aims to assess the effectiveness of topical non-antibiotic treatments compared to topical antibiotic treatment for the treatment of acute otitis externa.
Methods:
Systematic review and meta-analysis databases searched: Cochrane Library including
ClinicalTrials.gov; MEDLINE; World Health Organisation International ClinicalTrials Registry Platform and Web of Science to identify randomised clinical trials evalu- ating topical antibiotics and topical non-antibiotic agents in adults and children with acute otitis externa. Non-antibiotic therapeutics for comparison with topical antibiotics included antiseptics, steroids, non-pharmaceuticals and astringents.
Results:
Seventeen trials were eligible for inclusion, with 10 combined in meta- analysis. Data could be pooled comparing antiseptic and steroid monotherapies with topical antibiotic agents. There were no significant differences in cure rates in any pairwise comparisons. Individually, the majority of studies favoured topical antiseptics or steroids over antibiotics, however these differences were not significant when pooled in meta-analysis.
Conclusion:
Antiseptic, steroid and antibiotic monotherapies are all effective for the management of acute otitis externa. There is insufficient evidence to suggest that topical antiseptic or steroid agents are superior or inferior to topical antibiotics.
K E Y W O R D S
acute otitis externa, meta analysis, systematic review, topical antibiotics, topical therapies
1 | I N T R O D U C T I O N
Acute otitis externa (AOE) is inflammation of the outer ear canal, which often presents with symptoms such as itching, discharge, pain or hear- ing loss, and is of <6 weeks duration. In the UK, most cases are
managed in primary care, with only 3% of cases referred to ear nose and throat (ENT) surgeons.1–3
In UK primary care, it is estimated that up to 16%–40% of patients with AOE are treated with oral antibiotics by General Practi- tioners (GPs) while 14%–50% are treated with topical antibiotics and
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24%–42% receive no treatment. The latest guidance from the National Institute for Health and Care Excellence (NICE) recommends the promotion of self-care with over-the-counter acetic acid ear drops or spray for those aged 12 years and older, and the prescription of topical antibiotics with or without steroid as first line medical ther- apy.7NICE only recommends oral antibiotics for AOE with systemic features or cellulitis extending beyond the ear canal. To date, there has been no high level evidence to suggest that antibiotic treatment (topical or oral) is more effective than non-antibiotic agents such as antiseptics or steroids,8,9which could explain the lack of clear indica- tion for antibiotics by NICE. Non-antibiotic alternatives are always preferable where clinically appropriate due to the growing concern of antimicrobial resistance. The potential for topical antibiotics to induce systemic bacterial resistance, was proposed in several ophthalmologi- cal studies, and is still under review in the literature.10
1.1 | Objective
To perform a systematic review and meta-analysis of the effective- ness of topical non-antibiotic agents when compared to topical antibi- otic treatment as treatments for AOE.
2 | M E T H O D S
We performed a systematic review of randomised controlled trials (RCTs) investigating topical antibiotic treatments with topical non- antibiotic treatments in adults and children with AOE.
The systematic review protocol was prospectively registered in the PROSPERO database (ID: CRD42022351896) and the review was prepared according to PRISMA guidance.
2.1 | Population
We included RCTs investigating topical treatments for adults and chil- dren with acute otitis externa. As stated a priori, we excluded trials investigating chronic suppurative otitis, malignant, fungal, viral or necrotising otitis externa.
2.2 | Intervention/comparator
Trials comparing topical antibiotic treatment with non-antibiotic alter- natives such as antiseptics, steroids, astringents or herbal remedies were eligible. Co-interventions such as ear cleaning were permitted.
2.3 | Outcome
We included RCTs that measured at least one outcome variable such as cure or improvement in symptoms or signs.
2.4 | Search methods
Systematic electronic searches were performed in the Cochrane Library includingClinicalTrials.gov, MEDLINE, EMBASE, World Health Organi- sation (WHO) International Clinical Trials Registry Platform (ICTRP) and Web of Science. There were no publication limits imposed and the search strategies were peer reviewed by an experienced information specialist librarian. The search strategies were adapted with the subject strategies designed by the Cochrane Highly Sensitive Search Strategies for identifying randomised trials in MEDLINE. In the grey literature search (for the purpose of this study defined as formal documents iden- tified outside academic journals: conference proceedings, literature from official bodies etc.), we identified additional studies from the refer- ence lists of selected publications, and Google and Google Scholar.
Two authors separately reviewed titles, abstracts, and full manu- scripts via Rayyan software (https://www.rayyan.ai/). We excluded non-English languages, and articles not fulfilling our PICO criteria.
2.5 | Data extraction
Two authors independently extracted data from eligible studies using a data extraction form adapted from the Cochrane template. We extracted data on setting; population (sample size, age, gender; inclu- sion/exclusion criteria); interventions and outcome measures and recorded this in tables for narrative review.
2.6 | Risk of bias
Two authors used the Cochrane Handbook for Systematic Reviews of Interventions‘to independently appraise RCT quality. We assessed the quality of randomisation, blinding, follow up and outcome measurement and summarised the overall risk of bias in a RoB2 traffic plot.
Key points
• Acute otitis externa is an important condition in general practice and tertiary ENT care.
• The indication for antibiotics for the management of uncomplicated AOE is not currently supported by robust evidence.
• In the course of this review and meta-analysis no single non-antibiotic intervention was inferior to antibiotics.
• Before additional systematic reviews are conducted, more high quality RCTs are needed in primary settings, with standardised inclusion/exclusion criteria, outcome measures and co-interventions such as aural toilet.
• RCTs trialling ichthammol-glycerine could benefit from standardising the route of antibiotic delivery, to allow future meta-analyses.
2.7 | Data analysis
For primary outcomes, we recorded either binary frequencies or contin- uous mean/median symptoms scores with 95% confidence intervals where possible. We performed meta-analysis in R (R project for statisti- cal computing, Vienna, Austria) by pooling studies with the same drug categories and comparable outcome variables using random effects models. We previously stated in our protocol that we would pool studies with heterogeneity of <50% (I2); however, we combined studies regard- less of heterogeneity to visually depict the trends in forest plots. We are clear that conclusions on these analyses should be drawn with caution.
3 | R E S U L T S
In full text evaluation, we identified 17 eligible RCTs for systematic review.
We excluded 2035 articles during title and abstract screening. At full text screening, 34 articles were excluded (PRISMA flow chart, Figure1).
3.1 | Quality assessment
Risk of bias assessment for included studies is summarised in Table1.
Figure2demonstrates overall risk of bias. Four RCTs were of high quality, six were of intermediate quality and seven were of low quality (Figure2). Four studies were low risk11–14due to limited concerns:
missing outcome data <15% of participants11; single-blinded doctors measured outcome data13; omission of information on randomisation/
allocation concealment but balanced participant characteristics.12,14 Intermediate risk of bias was mostly assigned due to lack of information.
3.2 | Study characteristics
We have summarised the descriptive data in three tables: population and interventions (Table2); diagnostic and exclusion criteria (Table3);
outcome variables and adverse events (Table4).
F I G U R E 1 PRISMA flow chart of article selection for systematic review.
TABLE1Methodologicalqualityofstudiesandriskofbiasineachdomain. StudyIDSequencegeneration Allocation concealmentBaselinedemographicsBlindingMissingoutcomedata
Measurementandreportingof outcomes Dadagianetal.20Unclearhow randomisationtook place,andwhether groupswere randomisedwithin groups1and2
LowriskUnclear,nobaseline characteristicdata LowriskUnclearwhichtreatmentsarmshad exclusionsandreasons.Thereasonsfor exclusionsarenotstated.
Lowrisk Outcomemeasurementtakenby blindedprofessional;thesame outcomesreportedareoutlinedin methods
Medicationbottles werecodedby independent assistant
Doubleblinded Lambert16UnclearUnclearLowriskUnclearHighriskUnclearifoutcomemeasurementis takenbyblindedprofessional;the sameoutcomesreportedare outlinedinmethods Otosporin®group:Sixlosttofollowup. Threechangedtoaluminiumacetateand startedtoimprove
Nocorrelationbetween ageandresponseto treatment Baselinecharacteristic notreported
Aluminiumacetategroup:Threelostto followup.ThreechangedtoOtosporin® becausealuminiumstung Slack24UnclearMediumriskUnclearLowriskMediumriskUnclear Patientswereaware ofthelettercode ofthedrops,but clinicianswerenot
Nobaseline characteristicsdata Singleblinded: doctorsonly
Fourlosttofollowup,unclearwhich treatmentarmsthesepatientsdropped outfrom4/28(14%) Claytonetal.25UnclearLowriskUnclearLowriskHighriskUnclearifoutcomeassessorwas blinded Pharmacistskeptthe medicationcodes
Nobaseline characteristicsdata
Doubleblinded37/139(26.6%)earsexcluded.Significantly moreearsweretreatedwithgentamicin p=.003 Ruthetal.3UnclearLowriskLowriskLowriskMediumriskMediumrisk Dropswereplacedin numberedboxes
Balancedbaseline characteristics Singleblinded: doctorsonly
7/53(13%)losttofollowupTwoblindedENTdoctorswere responsibleforoutcome measurement Unblindedpatientscontributedto outcome Tsikoudasetal.22LowriskLowriskLowriskLowriskMediumriskLowrisk Computergenerated randomisationcode
Thepharmacists concealedthe groups BalancedforgenderDoubleblinded13/39(33%)exclusionsThepatientsanddoctorsassessed clinicaloutcomesandwereblinded totreatmentFourpatientslostafterfirstvisit,twofrom eacharm Ninelosttofollowup.Fivewerein antibioticgroupandfourinsteroid
TABLE1(Continued) StudyIDSequencegeneration Allocation concealmentBaselinedemographicsBlindingMissingoutcomedata
Measurementandreportingof outcomes VanBalenetal.11LowriskLowriskLowriskLowriskMediumriskLowrisk Computergenerated randomisationlist: ratioof1:3
Pharmacistssupplied dropscoveredin brownpaper Unbalancedbaseline characteristics,but regressionmodels wereusedtoadjustfor confounding
Doubleblinded23/213(10.7%)exclusionsDoctorsinvolvedinclinical examinationwereblindedtothe treatmentsreceivedSixteendiscontinuedtreatment;sevenlost tofollowup Neheretal.12Unclearhow randomisationcode wasgenerated
UnclearLowriskLowriskLowriskLowrisk Balancedbaseline characteristics
DoubleblindedITTanalysisbydefault—noexclusionsDoctorsinvolvedinclinical examinationwereblindedtothe treatmentsreceived Low EmgardandHellstrom15LowriskHighriskLowriskHighriskLowriskHighrisk Balancedforageand gender OpenRCTOnepatientexcludedduetolackofpost baselinedata Patientsanddoctorsassessed responsestotreatmentandwere awareofthetreatmentsallocated
Computergenerated randomised scheduleFourlosttofollowup,twofromeacharm, butanalysedITT Johnstonetal.13LowriskLowriskUnclearLowriskLowriskOutcomeassessorswereblinded Randomisationwas doneusingExcelby pre-trialcreationof numberedseriesof envelopesassigned randomlytoeither treatmentarms Envelopesusedto concealthe treatments
Nobaselinecharacteristic data Singleblinded: doctorsonly
4/53hadmissingoutcomedata;analysed withITTanalysedwithITT Kantasetal.2UnclearUnclearLowriskHighriskUnclearHighrisk ENTdoctorsassessingpatientscould notbeblindedbecauseofthe differenttreatmentmodalities
Balancedforageand gender
Singleblinded: patientsonly Nosignificantdifferences foundinage/gender betweentreatment arms Abelardoetal.23LowriskUnclearLowriskLowriskHighriskLowrisk Balancedorageand gender Doubleblind7/37(18.9%)exclusions.Onepatientwas randomisedsequentiallytobothgroups; sixpatientswerelosttofollowup.Four inantibioticgroup;twoinsteroidgroup Outcomesstatedinprotocolare reportedinresults
Computergenerated randomisationcode BlindedoutcomeassessorsNosignificantdifferences foundinagebetween treatmentarms (Continues)
TABLE1(Continued) StudyIDSequencegeneration Allocation concealmentBaselinedemographicsBlindingMissingoutcomedata
Measurementandreportingof outcomes Mösgesetal.14UnclearUnclearLowriskLowriskLowriskLowrisk Balanceddemographic data
Doubleblinded20/244(8.2%)exclusions.Seven discontinuedingroupglycerol,13 discontinuedinantibioticgroup.Analysed withITT
Blindedoutcomeassessors Panahietal.17LowriskUnclearLowriskUnclearMediumriskUnclear Balancedforageand gender
Patientswere alternatively allocatedto treatments encodedasAorB withfirstcode chosenrandomly
10/80(12.5%)exclusions Nosignificantcorrelation wasfoundwith outcomedata AmaniandMoeini21LowriskLowriskLowriskLowriskUnclearLowrisk Patientswere randomlydivided intotwogroups basedontheeven andoddnumbers ofreception,or basedontheirturn ofexaminationthat wasinoddand evendays
Drugdropswere packaged identicallyand weretaggedby pharmacist Balanceddemographic data.Nosignificant differencefoundinage orgenderbetween treatmentarms
DoubleblindedExclusionswerenotspecifiedThepatientsanddoctorsassessed clinicaloutcomesandwereblinded totreatment Khaliletal.18LowriskUnclearUnclearUnclearUnclearUnclear LotterymethodExclusionsnotspecified Akshayaetal.19UnclearUnclearLowriskUnclearUnclearUnclear Balancedforageand gender Abbreviation:ITT,intention-to-treat.
Overall, 10 studies were double-blinded, one was an open trial15and four studies did not specify blinding status.16–19Fives studies were per- formed in the UK; two studies were based in each of Iran, Pakistan and Sweden. Cyprus, Greece, The Netherlands, Austria, Germany and the US produced one study each. Eight studies were restricted to adults, accord- ing to a threshold age of 17/18. Fourteen studies were based in tertiary care, two in in primary care,11,16and one was unspecified.20The sample sizes ranged from 28 to 236. Five studies reported funding: two from a
pharmaceutical company14,15 and three trials from charities.11,12,17No conflicts of interest were declared for any RCT.
3.3 | Diagnostic criteria
Nine trials did not specify diagnostic criteria for otitis externa, and those that did had no unifying diagnosis among them. Only two RCTs F I G U R E 2 Traffic light plot
depicting risk of biases in each study, generated in Robvis (risk of bias tools–robvis
[visualisation tool]).
TABLE2Studycharacteristicdataincludingparticipantcharacteristicsandinterventions. StudyID Setting SamplenumberAgeInterventionsandcomparator Interventionsdurationand frequency Auraltoilet Primaryvs. secondarycare
Y=yes N=noCountry Dadagian etal.20Unitedstates206earsrandomised3–89Group1:aceticacid(V)vs.acetic acidinaluminiumacetate(D)
Dropswereaddedviawickfor 24huntilday4
Y-allpatients 80earsassessedin Group1.(V=40ears) (D=40ears)
Afterday4thewickwastaken outandtheyaddedfivedrops directlyintotheearcanalQDS for3days
Group2:hydrocortisone+ aceticacid(VHC)vs.colistin, neomycinandhydrocortisone (CMS)102earsassessedin group2.(VHC=49) (CMS=53ears) Lambert16Primary126individuals randomised
1–44Otosporin(polymyxin,neomycin andhydrocortisone)vs. aluminiumacetate Dropswereself-administered TDSfor14days
Y-ifwaxblocked theeardrumGarrisonmedicalcentre inEpiskopiandfamily medicalcentrein BerengariaCyprus
117individualsassessed Slack24Tertiary28individuals–Boricacid(groupA)polymyxinB, neomycin,andhydrocortisone (groupB)polymyxinb; fluocinoloneeconazole; methanol;glycerol, polyethyleneglycol(groupC) Twodropswereself- administeredQDSuntilthe nextweeklyvisit
Y-allpatients UK24analysed GroupA(n=9) GroupB(n=7) GroupC(n=8) Claytonetal.25Tertiary137ears–Aluminiumacetatevs. Gentamicin
Patientsself-administeredfive dropsofeitheraluminiumor gentamicinTDSfor21days
N BradfordRoyalInfirmary102earsanalysed UK Ruthetal.3Tertiary,outpatients Sahlgrenskahospital Sweden
53patientsrandomised 46patientsassessed 11–74Oxytetracycline,hydrocortisone acetate,polymyxinB(TPB)vs. hydrocortisone(Locoid– hydrocortisone) Patientsself-administered3–5 dropsTDSfor7days
N Tsikoudas etal.22Tertiary,outpatients39patientsrandomised>18Vista-methasone®vs.vista- methasoneN®Dropnumbersandfrequency notdescribed
Y-allpatients HullRoyalInfirmaryVita-methasone® (n=17)UK Vista-methasone-N® (n=22) VanBalen etal.11Primary213adultsrandomised>17yearsAceticacidvs.triamcinolone acetonide+aceticacidvs. dexamethasone,neomycin andpolymyxinB
Patientsself-administeredthree dropsTDSfor21days Y-ifeardrumwas occluded42familypracticesAceticacid(n=71) NetherlandsAceticacid+steroid (n=63)
TABLE2(Continued) StudyID Setting SamplenumberAgeInterventionsandcomparator Interventionsdurationand frequency Auraltoilet Primaryvs. secondarycare
Y=yes N=noCountry Steroid,aceticacid+ antibiotic(n=79) Neheretal.12TertiaryOutpatients50randomised8–89N-Chlorotaurine(NCT)vs. polymyxinB,neomycin, hydrocortisone(Otosporin®)
Rolledcottonwickssoakedwith treatmentwereinserteddaily untilsymptomsdisappeared. Overall,treatmentlasted 9days N UniversityHospitalof Innsbruck
Otosporin®(n=25) AustriaNCT(n=25) Emgardand Hellstrom15Tertiary51patientsrandomised18–67Betamethasone(BD)vs. hydrocortisone, oxytetracycline,polymyxinB (HCPB) Oneunitofpipetteof betamethasonewasself- administeredBDuntilday4, thenifnocure,thiswas changedtooneunitODfor another7days
N EightENTdepartmentsBD(n=26) SwedenHCPB(n=25) 50patientsassessed 2–4dropsofHCPBwere administeredTDSfor7days Johnston etal.13Tertiary,emergencyclinic53individuals randomisedand assessed
>16yearsAceticacid(EarCalm®)vs.acetic acid+dexamethasoneand neomycin(Otomize®) Self-administeredonepuff/ spraysTDSfor2weeks
Y-allpatients UK Otomize®(n=21) EarCalm®(n=32) Kantasetal.2Tertiary,emergency wards
215patientsrandomised17–78Tricholoricacid(TCA)vs. PolymyxinB,neomycin, fluocinolone(Synalar®)as control Theearcanalwasinstilledwith TCAandthenwashedwith boricacid
Y-allpatients GreeceTCA(n=117) Synalar®(n=98)Synalar®dropswereusedTDS for10days Inseverecases,ribbongauze wassoakedwitheither Synalar®orTCAandusedfor 3daysandfollowingthisthe usualregimensdescribedfor eachdrugwereusedforthe remaining7days Antibioticswereusedinsome severecaseswithpinna cellulitis/lymphadenitis Tertiary44patientsrandomised19–91ThreedropsTDSfor2weeks (Continues)
TABLE2(Continued) StudyID Setting SamplenumberAgeInterventionsandcomparator Interventionsdurationand frequency Auraltoilet Primaryvs. secondarycare
Y=yes N=noCountry Abelardo etal.23Betamethasone(vista- methasone®)vs. betamethasoneandneomycin (vista-methasoneN®) Y-whentheear drumwas occluded
SouthmeadHospital, Emergencyclinic
Vista-methasone® (n=23) UKVista-methasoneN® (n=22) 37individualswere analysed Mösgesetal.14Tertiary244patientsrandomised19–84PolymyxinB(PS)vs.glycerolTwodropsTDSfor7daysN 19ENTcentres GermanyFirstphase:121patients randomised:Glycerol (n=62)Antibiotics (n=59) Secondphase:115 patientsrandomised: Glycerol(n=56) Antibiotics(n=59) 223patientswere analysed Panahietal.17Tertiary,Outpatients80patientsrandomised18–60Ciprofloxacin0.3%vs.Lamigex® (S.aromaticum,Langustifolia, Grobertianumessentialoils) Threedropswereself- administeredBDfor7days
N Iftherewasnoresponseto Lamigex®byday7,patents receivedciprofloxacininstead
Baqiyatallahhospital70patientsassessed Iran Amaniand Moeini21Tertiary80patientsrandomised19–65Boricacid(BA)vs.polymyxinB, neomycin,andhydrocortisone (PNH) Threedropswereself- administeredTDSfor10days
Y-incaseswith severeinflammation KashaniHospital Broadspectrumsystemic antibioticswasusedalongside topicaltherapywherethere wasfever,cellulitisor lymphadenopathy
Iran Khaliletal.18Tertiary,Outpatients100patientsrandomised12–50GroupA:10%ichthammol- glycerine(IG)wick GroupA:IGwickwaspackedin earandchangedevery48hrs for5days N FaujiFoundation Hospital GroupB:ciprofloxacinand dexamethasone
GroupBreceivedsteroid- antibioticdropsTDSfor 5days
GroupA(n=50)Pakistan GroupB(n=50)
specified AOE aetiology as eczematous or bacterial.3,20Fifteen studies outlined their exclusion criteria: nine excluded middle ear disease; four excluded patients with previous treatment for AOE in the last 2– 4 weeks and perforated tympanic membranes. We excluded studies investigating complicated AOE but included Johnston et al. as patients with mastoid cavity infections were randomised and reported separately.
3.4 | Interventions
The most investigated non-antibiotic treatments were antiseptics (9 studies), followed by steroids (4) ichthammol-glycerine (IG) (3) and a non-pharmaceutical (1).
The most common co-intervention was aural toilet; this occurred in 10 studies; 6/10 trials performed aural toilet in all patients; 4/10 performed ear cleaning as needed when the tympanic membrane was occluded. Four RCTs inserted wicks for severe canal oedema.3,11,16,21 Three studies administered interventions via medicated wicks.12,18,20 Five studies measured patient compliance with treatment, typically by weighing medication; one RCT also reviewed patient diary cards.15
3.5 | Outcomes
Outcomes were primarily reported as dichotomous cure rates (13 studies) or as mean/median symptom scores.2,12,14,22,23
Three studies used severity scores as an outcome variable.15,19,24 Three studies included improvement in individual symptoms, but no overall cure.17,20,21Three RCTs reported secondary outcomes includ- ing recurrence11,15,24and time till cure.2,11,12
Five studies cultured samples at enrolment and follow up as a test of cure. Five RCTs cultured samples only at enrolment to evaluate randomisation and incidence of pathogens.12,14,16,24Adverse events were reported in seven trials including mild symptoms of erythema, pruritis and hearing impairment. Side effects seldom influenced patients to change treatment.11,16,24Follow up ranged from 48 h to 6 months. Ten studies had at least one follow up at 7 days after treat- ment initiation.
3.6 | Topical antiseptics versus antibiotics
We pooled data from four RCTs with cure rates at day seven. These investigated polymyxin B/neomycin vs. an antiseptic.11,12,16,24
The antiseptics were boric acid,24aluminium acetate,16acetic acid,11and N-chlorotaurine.12 Antibiotic adjuvants included hydrocorti- sone12,16,24or dexamethasone.11Three studies included aural toilet, either in all patients24or as needed.11,16Two studies were high qual- ity; the remainder were moderate-low quality. Neher et al. reported symptom scores as continuous data; we used the number of patients with an inflammation score of zero to calculate the proportion of cured patients. We then pooled cure rates at day seven for
TABLE2(Continued) StudyID
Setting SamplenumberAgeInterventionsandcomparator Interventionsdurationand frequency Auraltoilet Primaryvs. secondarycare
Y=yes N=noCountry Akshayaetal.19Tertiary100patientsrandomised10–80GroupA:Betnovate-N® (betamethasonevalerateand neomycin)
Auralpackingwasperformed untilcanaloedemawas resolved
Y-allpatients SaveethaMedicalCollege andHospital NofrequencyspecifiedPakistan85patientsassessedGroupB:10%ichthammol glycerolpack Abbreviations:BD,twiceaday;OD,onceaday;QDS,fourtimesaday;TDS,threetimesaday.
T A B L E 3 Participant eligibility data including diagnostic criteria for otitis externa and excluded patients.
Study ID
Definition of acute
otitis externa (AOE) Inclusion criteria Exclusion criteria PPA or ITT
Number of patients excluded from analysis
Dadagian et al.20 Not specified Not specified Not specified PPA Unclear
Lambert16 Defined as
inflammation of external ear in combination with tragal tenderness
Acute otitis externa Middle ear pathology PPA Nine cases lost to follow up
Slack24 Not specified Not specified Patients with previous mastoid surgery and perforated tympanic membranes. Patients receiving treatment 2 weeks prior to enrolment
PPA Four exclusions due to
cholesteatoma Two exclusions due to
perforations One discontinued
treatment after day 1 due to pain One did not attend the
first follow up Clayton et al.25 AOE defined as
presence of otorrhoea
Patients with otorrhoea causing otitis externa; a discharging central perforation or discharging mastoid cavity
Patients who received topical or systemic antibiotics in previous 3 weeks; fungal external otitis; drug sensitivity to the medications used in the study; middle ear disease
PPA 37 exclusions, as failed to complete study. The authors report that there was no differential dropout rate between the arms
Ruth et al.3 Not specified Patients with mild or moderate otitis externa
Patients with fever, perichondritis, and/or a history of external otitis within the preceding month
PPA Seven lost to follow up and were excluded
Tsikoudas et al.22 Presence of oedematous ear canal with moist keratin debris
Patients diagnosed with otitis externa according to their diagnostic criteria
<18 years; neomycin allergy; ear canal oedema severe enough to prevent the use of topical ear drops;
middle ear disease
PPA Two lost from each group
after the first visit Nine patients lost to follow
up
Van Balen et al.11 Defined as presence of redness or swelling of auditory canal and symptoms of pain, pruritis, otorrhoea and hearing loss for
<3 weeks
Signs and symptoms of AOE
Symptoms of AOE >3 weeks; otitis media; <17 years old;
pregnancy; furuncle, perforated eardrum;
perichondritis; fever;
allergy to any of study drugs. Treatment for AOE in past month
PPA Seven lost to follow up
16 discontinued treatments
Neher et al.12 Not specified Acute otitis externa Malignant otitis externa;
topical treatment with other agents; systemic application of antibiotics or corticoids; pregnancy;
and participation in another study at the same time
ITT Not specified
Emgard and Hellstrom15Not specified To be included in the study the degree of inflammation had to reach a minimum
Subjects treated for EO within 30 days of enrolling in the study;
the use of anti-
ITT One patient randomised to
HCPB was excluded due to lack of post-baseline efficacy data
T A B L E 3 (Continued) Study ID
Definition of acute
otitis externa (AOE) Inclusion criteria Exclusion criteria PPA or ITT
Number of patients excluded from analysis score of 3.0
according to the status classification of the EAC
inflammatory/
antibiotic/antimycotic agent with possible interaction with inter and interventions used.
Perforated tympanic membrane; hearing aids; mastoiditis, psychosis; intellectual problems; pregnancy or breast feeding
Four patients—2 in each arm—were lost to 6-month follow up, but was included in complementary analysis
Johnston et al.13 Not specified Patients with acute AOE or infected mastoid cavities
Cholesteatoma; aural polyps; congenital anomalies, significant canal stenosis; chronic, acute on chronic or necrotising otitis externa; concomitant systemic disease;
immunocompromised;
<16 years; pregnancy
ITT Four patients in acetic acid group had missing outcome data
Kantas et al.2 Diagnosis required oedema, debris, pain, hearing impairment and ear discharge
17 years and older with otitis externa
Diabetics; coexisting middle ear pathology;
bilateral disease
Not specified Not specified
Abelardo et al.23 Defined as presence of oedema, discharge, or debris
>18-year-olds diagnosed with acute otitis externa according to their diagnostic criteria
Diabetes;
immunocompromise;
middle ear disease;
neomycin allergy
PPA Vista-methasone®group:
five excluded due to bilateral disease; two lost to follow up Vista-methasone N®
group: six excluded due to bilateral disease; four lost to follow up Mösges et al.14 Not specified Not specified Viral, fungal, or
tubercular ear infection; otitis media;
mastoiditis; mastoid cavities; stenosing exostosis;
cholesteatoma;
perforated tympanic membrane; invasive, malignant, or chronic otitis externa; pre- treatment of the current otitis externa with antibiotics or corticosteroids
ITT and PPA. 236 patients analysed with ITT
Glycerol group: 114 fulfilled protocols. 10 had missing data PS group: 109 fulfilled
protocols. 13 had missing data
Panahi et al.17 Presence of symptoms of pain and itching with signs of oedema, discharge, and tenderness
Patients diagnosed with otitis externa according to their diagnostic criteria
Not specified PPA 10 patients were excluded;
reasons were not specified
Amani and Moeini21 Not specified >17 years old with a diagnosis of acute otitis externa
Treatment with topical treatment within the last two weeks or oral antibiotics; diabetics;
immunodeficiencies;
Not specified Not specified
(Continues)
meta-analysis. The forest plot shows considerable heterogeneity (I2=81%) (Figure3). Although cure rates were mostly higher with antiseptic-use, this is not significant.
We pooled three studies which reported the number of cured ears from days 7 to 2113,20,25(Figure4). The antibiotic preparations included colistin/neomycin/hydrocortisone20; gentamicin25; neomy- cin/dexamethasone/acetic acid.13The antiseptic was acetic acid13,20 or aluminium acetate.25 All patients received aural toilet in two RCTs.13,20 Meta-analysis demonstrated high heterogeneity of 85%
(I2), and overall, there were no significant differences found. Taken individually, only Johnston et al. produced a significant difference, which favoured topical antibiotics.
The considerable heterogeneity could be explained in part by inclu- sion of Dadagian et al.20The antiseptic was combined with hydrocorti- sone, which may have acted synergistically with acetic acid. Also, their population included seborrheoic AOE. They reported outcomes as indi- vidual symptoms; we used their overall percentage of improved symp- toms to calculate the proportion of ears cured overall. The other RCTs measured inactive disease13or symptom improvement as cure.25
We could not combine Amani and Moeini continuous data, which was reported as individual symptoms.21 They trialled boric acid against Otosporin® (polymyxin B/neomycin/hydrocortisone) and
found oedema was significantly improved with boric acid from day three onwards (p=.001; Table S5). The secondary outcome, pain, measured by McGill pain questionnaire, was also significantly better in the boric acid arm from day seven (p=.001).
Two studies reported infection scores in patients treated with either Synalar® (Polymyxin B/neomycin/fluocinolone) or Otosporin® and an antiseptic and thus could not be pooled. The median infection scores were significantly better after one-week treatment with tricho- loric acid when compared to Synalar® (0; 0–0 vs. 1; 0–5p=.000;
Table S6).2Similarly, patients treated with 9 days of N-cholorotaurine had significantly improved infection scores relative to those treated with Otosporin®(0; 0–1 vs. 1; 0–4;p> .001).12Furthermore, the time till cure was shorter with N-cholorotaurine with respect to Otos- porin®(5.6 (3–9) vs. 7.4 (4–10),p=.001; Table S7).
In contrast, van Balen et al.'s study showed that patients treated with dexamethasone/neomycin/polymyxin-B recovered more quickly than those treated with acetic acid (6 days (5.1–6.9) vs. 9 days (7–9), p=.0005).11 This study differed by the addition of aural toilet and the adjuvant dexamethasone, a stronger steroid than hydrocorti- sone.11They also measured long term efficacy and demonstrated that topical antiseptics resulted in more relapses by week 6 (OR 1 vs. 0.4 (0.2–1p=.052; Table S8).11
T A B L E 3 (Continued) Study ID
Definition of acute
otitis externa (AOE) Inclusion criteria Exclusion criteria PPA or ITT
Number of patients excluded from analysis previously medicated
with oral corticosteroids or immunosuppressives;
perforated eardrum;
external otitis exceeding 3 weeks;
furunculus ear canal Khalil et al.18 Not specified Cases of diffuse AOE
with oedema of external auditory canal >75%
AOE >3 weeks; otitis media; foreign body ear; impacted wax, congenital ear deformities; diabetics
Not specified Unclear
Pain score of >4 on NRS
Akshaya et al.19 Diagnosed with rapid occurrence of symptoms such as severe ear pain, aural fullness, hearing issues, pruritic, pain during jaw movements within 48–72 h. In combination with signs such as tragal tenderness, erythema/oedema of the external canal and ear discharge
Patients >10 years of age meeting diagnostic criteria
Bilateral disease; abscess;
otitis media; diabetics and
immunocompromised patients
Not specified Not specified
Abbreviations: HCPB, hydrocortisone, oxytetracycline, polymyxin B; ITT, intention-to-treat; PPA, per-protocol analysis; PS, polymyxin B.
TABLE4Clinicalandmicrobiologicaloutcomesassessed,includingadverseevents. StudyIDClinicaloutcomesprimarysecondaryClinicaloutcomescales
Timingofoutcomes measuredMicrobiologicaloutcomesAdverseevents Dadagian1974201.Clinicalcuredefinedbydoctoras meanabsenceof4symptoms:pain, pruritis,discharge,andoedema
NotspecifiedDays0,4and7Swabstakenatday4and7as testofcure
Notspecified Lambert161.Curedefinedasabsenceofpain, deafness,itchingordischargeand normalearcanalonexamination
NotspecifiedDays07and14Swabonlytakenatpresentation toshowrangeofspecimens found
Notspecified Slack241.Curedefinedasabsenceof symptoms:itchingburningdeafness, pain,discharge,andsigns:erythema, swelling,debris,pus 2.SeverityscoresofAOE 3.Secondaryoutcome:recurrenceby 4months
Scales0–3usedforboth symptomsandsigns. 0–3wasnotdefined Days0,7,14and21Swabonlytakenatpresentation, toshowrangeofspecimens found
Earstingingineightpatients(four ineachgroup).Onlyoneceased treatmentbecauseofthis Claytonetal.251.Curedefinedasimprovementin scoreof2orscoreof0inclinical signsofacuteotitisexterna.Signs includedpresenceofotorrhoeaand oedema
Otorrhoeaandoedemascoredon a0–4scale 0=Dryear 1=Moistearwithoutotorrhoea 2=Otorrhoeanoticedbypatient andsomeoedemaon observation 4=Otorrhoeawitheardrum completelyobscuredbyoedema ormastoidcavity Days0,9and21Swabstakenatenrolment,day9 andday21astestofcure
- Ruthetal.31.Self-evaluationofsymptomsofpain, itchingorsecretionsinpatient questionnaire 2.Signsofrednessorswellingon examination. Curedefinedasabsenceofthesesigns andsymptoms
NotspecifiedDay0and14Swabstakenatenrolmentand day14astestofcure
Hearingimpairmentandpain Hearingimpairmentwasmore commoninTPBgroup PainwasmorecommoninLocoid (hydrocortisone)group Tsikoudasetal.221.Symptomsofblockage,pain dischargeanditching 2.SignsofAOE-dependingondegree ofdebrisandcanaloedema Curewasdefinedbyimprovementin mediansymptomandassessment scorefrombaseline
Patientsself-evaluatedtheirfour symptomsusingalinear analoguescale Doctorsassesseddebrisandcanal oedemausinga10-cmlinear analogueassessmentsheet
Days0,3,7and11–Notreported VanBalenetal.111.Durationofsymptomsindays accordingtodiaryentries Secondaryoutcomes 2.Cureratesaccordingto questionnairescompletedbyGP.
Signsofswelling,desquamation, redness,narrownessand otorrhoeascoredon0–3scale 0=nosigns 2=moderatesigns Day07,14and21 Recurrencebetween days21–42days
–Sideeffectsin74%ofpatients;all minorevents.2inantiseptic groupand1patientin antiseptic/steroidgroup discontinuedtreatment (Continues)
TABLE4(Continued) StudyIDClinicaloutcomesprimarysecondaryClinicaloutcomescales
Timingofoutcomes measuredMicrobiologicaloutcomesAdverseevents Signsincluded:swelling, desquamation,redness,narrowness andotorrhoea 3.Recurrencebetweendays21and42
3=severesigns Neheretal.12Primaryoutcome 1.Curewasdefinedasmedianscoreof inflammationortolerability(pain) of0 Secondaryoutcome 1.Timetillcuredefinedastimeto achieveinflammationscoreof0 Inflammationwasmeasuredon 6-step-score0–5 5=seriousinflammationwithear canalobstructedbyoedema 0=nosignsofinflammation Painratedonvisualanaloguescale 0–10 0=nopain 10=intolerablepain DailyexaminationCulturesweretakenatbaseline toshowrangeofspecimens andensurebalanceacross treatmentarms
Theonlysideeffectwasadelayof healingofanartificial perforationofthetympanic membrane EmgardandHellstrom15Primaryoutcomes: 1.Curedefinedasscoreof1orbelow forthesymptomsandsignsofAOE 2.Symptomseverityscores Secondaryoutcome 1.Relapse-freesurvivalfor6months
Patientevaluation:painratedon 0–2scale 0=nodiscomfortatall;1=most symptomsalleviatedbutmild discomfortpersisting;2=some benefitfromthetreatmentbut numeroustroublesome VASusedbypatienttoestimate itching,abilitytowork,abilityto sleep SignsofAOEassessed:Physician evaluation ColouroftheEAC(0=noor slightblush;1=pink;2=red 3=purple) Theextentofrednessonthe pinna(0=normal;1=redness ofmeatusexterniandtragus; 2=extendingtocavumauris, 3=extendstomastoidprocess) TheswellingoftheEAC (0=normal;1=annulus fibrosusvisibleintwooffour quadrantsofthetympanic membrane;2=annulusfibrosus Days0,4,8(optional ifnocureonday4) 11 2monthlyfollowup for6months
Swabstakenatenrolmentand day11astestofcure Noseriousadverseevents described
TABLE4(Continued) StudyIDClinicaloutcomesprimarysecondaryClinicaloutcomescales
Timingofoutcomes measuredMicrobiologicaloutcomesAdverseevents notvisibleinanyquadrant, 3=EARoccluded) Thepresenceofeffusioninthe EAC(0=dry;1=moisture, 2=fluidpresent,requiring suction;3=otorrhoea) Johnstonetal.131.Inactivedisease/resolutionofall signsofAOEonexamination
Day14and28–Notreported Kantasetal.2Primaryoutcome 1.Curedefinedasimprovementin infectionscoreandtolerability(pain) wasmeasuredonVAS Secondaryoutcome 2.Thetimeindaystillcurerequireda scoreof0acrossinfectionscore andpain
Infectionscoremeasuredon0–5 scale 0=noinflammation 5=severeinflammationwith completeobstructionby swelling VASscoreforpain:0=nopain; 10=intolerablepain Days0,3,5,7,10 and20
Bacterialcultureswereonly obtainedinrecurrenceafter 20days;resultsarenot reported
Nonedevelopedchemicalpeeling orhearingimpairment.4 patientsreceivingSynalar®had erythemafromallergicreaction toneomycin Abelardoetal.231.Curedefinedasimprovementof symptomsofblockage,pain, discharge,itching.Describedas patientfrequenciesandmedian symptomscores
Patientsratedtheirsymptoms usingalinearanaloguescale, theydidthisweeklytill resolution
Day0,7and14–Noadverseevents Mösgesetal.141.Absolutechangeinclinicalsymptom scores(CSS),ofredness,swelling, painandsecretion Secondaryoutcomes 2.Patientreportedpainmeasured onVAS
CSSscale:0=none1=mild 2=moderate 3=severe VASscaleforpain:0cm=nopain 10cm=verystrongpain Day0,4and10Cultureswereusedtostratify thestudypopulationinto clearlybacterialandprobably non-bacterialcases
11adverseevents(2inglycerol group;9inPS)Nonewere seriousorfatal Panahietal.171.Curedefinedasimprovementor absenceofsignsofitchingdischarge, tenderness,redness,andoedema 2.PainonVAS
VASscaleforpain:100mm horizontalline 0mm=nopruritis 100mm=unbearablepruritis.
Days0,3and7Swabstakenatenrolmentand day7astestofcure
Notreported AmaniandMoeini211.Curedefinedasimprovementin individualsymptomofeardischarge, itching,hearingloss,earcanal swelling,auricleswellingandfever 2.Pain—measuredonMcGillpain questionnaire
TheMcGillpainquestionnairewas filledinbypatientsanddoctors. Thisconsistedoffourdomains, includingdescriptivecriteria; limitationofpainontheirQOL; impactonbehaviour.Scorewas outof18
Days0,3,7and10–Notreported Khaliletal.181.Curedefinedasimprovementin oedemaandpain
Painwasmeasuredbypatienton NRS Days1and5–Notreported (Continues)
3.7 | Topical steroid monotherapies versus antibiotic/steroid combination
We pooled 3/4 studies that investigated topical antibiotic/steroid combi- nations against topical steroids as they reported dichotomous cure rates from days 11 to 15 (Figure5).3,15,23Oxytetracycline/polymyxin B/hydro- cortisone3; oxytetracycline/hydrocortisone15and betamethasone/neomy- cin®23were compared to hydrocortisone,3and betamethasone.15,23 All three studies were of low quality.3,15,23There was moderate heterogene- ity (I2=62%) in this sample, and no significant differences in effective- ness either individually or overall. The variability might be explained by the different outcomes measures, which included patient-reported symp- tom improvement,23or patient/physician measured cures.3,15Also, Ruth et al. included one diabetic patient and seven patients with co-existing seborrhoeic eczema.
Two studies reported median symptom scores to measure the impact of betamethasone versus betamethasone-neomycin®, and could be not be pooled in meta-analysis (Table S9).22,23 Tsikoudas et al. reported lower symptom scores when betamethasone was used alone, however this was not significant (4 (0–19.1) vs. 8 (0–39.3), p=.164). In contrast, Abelardo et al. indicated that the addition of neomycin produced better median symptom scores at day 15 (3.5 vs. 2.7p=.88). Both were medium quality RCTs based in UK hospi- tals with similar sample sizes (33–39) and inclusion criteria. They per- formed aural toilet either in all patients,22or as needed.23However, Abelardo et al. excluded diabetic AOE and measured only patient- reported outcomes. Emgard and Hellstrom also measured relapse-free survival, this was significantly higher in the betamethasone cohort at 6 months (15/24 vs. 6/22;p=.02).15
3.8 | Topical ichthammol glycerine versus antibiotics
Three RCTs compared either IG pack18,19or glycerol drops against polymyxin B,14 betamethasone/valerate/neomycin,19 or ciprofloxa- cin/hydrocortisone.18We were unable to pool the results because of outcome heterogeneity.
The highest quality study, demonstrated that, by day 10, the reduction in severity scores were significantly greater in patients trea- ted with antibiotics (2.2 (2.6) vs. 1.5 (2.1),p=.0552; Table S10).14Of the four symptoms measured, only oedema significantly improved with antibiotics relative to glycerol. Akshaya et al. also favoured anti- biotics over IG; as pain was milder in the antibiotic group (23/42 vs. 36/43, p=.007; Table S11). There was only one study that favoured IG; they reported significantly improved pain/oedema reduc- tion when compared to antibiotic/steroids (Table S12).18
3.9 | Topical essential oils versus antibiotics
One RCT compared topical ciprofloxacin with Lamigex®, a mixture of three essential oils.17More patients were pain-free after week-long TABLE4(Continued) StudyIDClinicaloutcomesprimarysecondaryClinicaloutcomescales
Timingofoutcomes measuredMicrobiologicaloutcomesAdverseevents Akshayaetal.191.Painseverityscore 2.Numberofhospitalvisits
PainwasmeasuredwithNRS 0=nopain 1–3=mildpain 4–6=moderatepain >7=severepain 10=extremepain Days0every48h untilpainsubsided–Notreported Abbreviations:NRS,numericalratingscale;PS:PolymyxinB;QOL,qualityoflife;TPB,oxytetracycline,hydrocortisoneacetate,polymyxinB;VAS,visualanaloguescale.
treatment with ciprofloxacin with respect to Lamigex®; however, this was not significant (p=.543; Table S13). There were also no signifi- cant differences in tragal tenderness, itching, erythema, discharge and oedema between the groups (Table S14).
4 | D I S C U S S I O N
The aim of this meta-analysis was to compare topical antibiotics (with or without adjuvants) with a broad range of topical non-antibiotic agents in the treatment of AOE. Non-antibiotic treatments have proven effective in the management of various superficial infections:
honey and antiseptic iodine dressings are routinely applied to surgical wounds, and do not contribute to antimicrobial resistance.26,27
The three meta-analyses in this review demonstrated no significant difference in measured outcomes for antibiotic vs. non-antibiotic treat- ments. This is consistent with two previous meta-analyses that found topi- cal antiseptics were also non-inferior to antibiotics for AOE.8Rosenfeld et al. included 3/4 RCTs that we combined,11,12,24,28and an RCT we excluded as the population included fungal AOE.28The Cochrane review corroborated this with only three of these RCTs.11,12,24Rosenfeld et al.
demonstrated steroids were in fact superior to antibiotics at day 7–11
(p=.021).8In contrast, pooling the same RCTs,3,15and one additional study that favoured antibiotics over steroids,23produced equivalent effi- cacy in our meta-analysis (p=.07). Cochrane did not perform meta- analysis for steroids, as they were limited to one study.22It is possible that steroids and antiseptics are more effective than antibiotics given the over- all trend in individual RCTs: 7/9 favoured topical antiseptics, 3/4 favoured steroids. However, to enhance the evidence, higher quality studies with limited heterogeneity in population, intervention and outcomes should be pooled to discern if this trend is significant.
We are the first to review non-pharmaceuticals and IG, an antimi- crobial agent that reduces canal oedema and pain.29,30Two of three RCTs favoured topical antibiotics over IG, however we could not per- form meta-analysis due to heterogeneity, and we also had to exclude three further RCTs for including oral antibiotics alongside the inter- ventions for all patients.31–33
4.1 | Variations in studies
Ten studies performed aural toilet to allow visualisation of the ear canal and tympanic membrane. No study stratified the results accord- ing to this co-intervention. This made it difficult to assess potential F I G U R E 3 Random effects meta-analysis of topical antiseptic vs. topical antibiotic (control) for clinical cure of acute otitis externa. The overall odds ratio confidence intervals cross 1, and the absolute cure rate difference is not significant. There is significant heterogeneity in this sample (I2=81%,p< .01).
F I G U R E 4 Random effects meta-analysis of topical antiseptic versus topical antibiotic with or without steroid adjuvant (control) for cured ears. The overall odds ratio confidence intervals cross 1, and the absolute cure rate difference is not significant. There is significant heterogeneityI2=85% (p< .01).
confounding, particularly where aural toilet was conducted on an‘as needed’basis. Additionally, two studies administered oral antibiotics for cases including cellulitis but did not stratify these severe cases.2,21
Nine studies did not define AOE diagnosis or inclusion criteria, or the suspected aetiology. Two studies included eczematous AOE, with only one stratifying results by atopic/bacterial AOE.20This limited the external validity as atopic AOE may be more responsive to steroids.
Further confounding may have arisen from an RCT that included dia- betes comorbidity24 and another study that used 0.1% aluminium acetotartrate wicks as an adjunct in all patients.3The scarce defini- tions for AOE may explain some variation in outcomes, as trialists prioritised different clinical features.
A recent review attempted to create a consensus definition for AOE, as well as a core outcome set. Six outcome criteria were gener- ated by stakeholder consensus to help standardise future RCT design and reporting.34None of the included trials reported all six outcomes, only one RCT measured functional status, and none measured finan- cial impact.21
4.2 | Weaknesses in existing studies
Conclusions are limited by the quality of evidence, which was mostly intermediate-low. An important contributor was missing outcome data and limited blinding. Loss to follow up was balanced across both arms in only three of these trials.15,16,22Only four studies adopted an intention-to-treat analysis.11–14Nine studies did not specify dropout across groups. In 2 of 4 single-blinded RCTs,2,3,13,24 unblinded patients contributed to the primary outcome3,24and unblinded physi- cians measured outcomes in another.2One RCT was open,15and four did not specify blinding status.
4.3 | Clinical applicability
Only two RCTs were set in primary care, where most patients are managed with limited access to aural toilet.1 The population in our
review could therefore represent more severe cases seen in second- ary care, and one RCT even excluded mild–moderate AOE.15 The comparative effects of antibiotics/non-antibiotics could differ in milder infections.
However, generalisability of the review findings is strength- ened by the diverse locations covered by included RCTs, includ- ing low-resource settings, as well as the variety of participant characteristics and the causative organisms; where taken, swabs cultured typical AOE pathogens, predominantly pseudomonas aeruginosa.1
The non-antibiotic interventions were typically simple to use and although no formal cost-effectiveness analysis was performed, all pri- mary interventions are relatively low cost.35
4.4 | Recommendations for future studies
Future non-inferiority RCTs should be conducted in primary care, trialling antibiotic alternatives with standardised diagnostic/
exclusion criteria and outcome measures. Measuring the six out- come variables reported by Smith et al. would permit meta- analyses for further outcomes and increase the generalisability of results. Trialists should minimise biases from inadequate blinding, and minimise potential confounding, standardising the route of antibiotic administration and co-interventions such as aural toilet.
5 | C O N C L U S I O N
Antiseptic, steroid, and antibiotic agents are all effective for the man- agement of acute otitis externa, with no conclusive evidence of supe- riority of any agent. Use of non-antibiotic agents for AOE may form part of antibiotic stewardship strategies designed to reduce antibiotic resistance. Future studies should be conducted with robust methodol- ogy, in both primary and secondary care, to ensure the results are rel- evant to all AOE patients.
F I G U R E 5 Random effects meta-analysis of topical steroid alone vs. topical antibiotic/steroid (control) for clinical cure of acute otitis externa.
The overall odds ratio confidence intervals cross 1, and the absolute curate rate difference is not significant. The heterogeneity is 62% and this is not significantp=.07.
A U T H O R C O N T R I B U T I O N S
Designed the work,acquired,and analysed data: Rosalind Di Traglia, Ben Tudor-Green, Jameel Muzaffar, Daniele Borsetto, and Matthew E. Smith.Drafted and revised the manuscript: Rosalind Di Traglia, Ben Tudor-Green, Jameel Muzaffar, Daniele Borsetto, and Matthew E. Smith.Approved the manuscript to be published: Rosalind Di Traglia, Ben Tudor-Green, Jameel Muzaffar, Daniele Borsetto, and Matthew E. Smith.Accountable for all aspects of the work: Rosalind Di Traglia, Ben Tudor-Green, Jameel Muzaffar, Daniele Borsetto, and Matthew E. Smith.
A C K N O W L E D G E M E N T S
No funding was received for this work and there are no acknowledge- ments to make beyond the co-authors.
C O N F L I C T O F I N T E R E S T S T A T E M E N T
MS is an Associate Editor for Clinical Otolaryngology and a co-author of this article. They were excluded from editorial decision-making related to the acceptance and publication of this article. MS has received funding from Circius Pharma AB to support clinical research in AOE. Cirrius Pharma had no role in the development of this review.
P E E R R E V I E W
The peer review history for this article is available athttps://www.
webofscience.com/api/gateway/wos/peer-review/10.1111/coa.
14084.
D A T A A V A I L A B I L I T Y S T A T E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request. Additional data that supports the findings of this study are available in the supplementary material of this article
E T H I C S S T A T E M E N T
Ethics approval is not required for this article.
O R C I D
Rosalind Di Traglia https://orcid.org/0000-0001-5746-7160 Jameel Muzaffar https://orcid.org/0000-0003-3065-0269 Daniele Borsetto https://orcid.org/0000-0003-3464-2688 Matthew E. Smith https://orcid.org/0000-0001-8147-1549
R E F E R E N C E S
1. Rowlands S, Devalia H, Smith C, Hubbard R, Dean A. Otitis externa in UK general practice: a survey using the UK general practice research database. Br J Gen Pract. 2001;51(468):533–8.
2. Kantas I, Balatsouras D, Vafiadis M, Apostolidou M, Pournaras A, Danielidis V. The use of trichloroacetic acid in the treatment of acute external otitis. Eur Arch Otorhinolaryngol. 2007;264(1):9–14.
3. Ruth M, Ekstrom T, Aberg B, Edstrom S. A clinical comparison of hydrocortisone butyrate with oxytetracycline/hydrocortisone acetate-polymyxin B in the local treatment of acute external otitis.
Eur Arch Otorhinolaryngol. 1990;247(2):77–80.
4. Tierney PA, Price T, Gillet D, Oyarzabal MO, Salama N. Improving standards in the treatment of acute otitis externa by the use of a
treatment protocol and open access to aural toilet. J Laryngol Otol.
2001;115(2):87–90.
5. Trinidade A, Qayyum A, Lee A, Shakeel M, Osbourne S, Kotecha B.
Audit of otitis externa referrals and management in a tertiary care set- ting. J Otolaryngol Head Neck Surg. 2011;40(4):288–94.
6. Pabla L, Jindal M, Latif K. The management of otitis externa in UK general practice. Eur Arch Otorhinolaryngol. 2012;269(3):753–6.
7. National Institute for Health and Care Excellence (NICE). Scenario:
Acute otitis externa; 2022. [cited 2022 Oct 25]. Available from:
https://cks.nice.org.uk/topics/otitis-externa/management/acute-otiti s-externa/
8. Rosenfeld RM, Singer M, Wasserman JM, Stinnett SS. Systematic review of topical antimicrobial therapy for acute otitis externa. Oto- laryngol Head Neck Surg. 2006;134(4):S24–48.
9. Kaushik V, Malik T, Saeed SR. Interventions for acute otitis externa.
Cochrane Database Syst Rev. 2010;(1):CD004740.
10. Brown L. Resistance to ocular antibiotics: an overview. Clin Exp Optom. 2007;90(4):258–62.
11. van Balen FA, Smit WM, Zuithoff NP, Verheij TJ. The effectiveness of three common treatments of acute otitis externa in general practice:
a controlled, randomized trial. Huisarts en Wetenschap. 2004;47(12):
550–4.
12. Neher A, Nagl M, Appenroth E, Gstöttner M, Wischatta M, Reisigl F, et al. Acute otitis externa: efficacy and tolerability of N-chlorotaurine, a novel endogenous antiseptic agent. Laryngoscope. 2004;114(5):
850–4.
13. Johnston M, Flook E, Mehta D, Mortimore S. Prospective randomised single-blind controlled trial of glacial acetic acid versus glacial acetic acid, neomycin sulphate and dexamethasone spray in otitis externa and infected mastoid cavities. Clin Otolaryngol. 2006;31(6):504–7.
14. Mösges R, Baues C, Schröder T, Sahin K. Acute bacterial otitis externa: efficacy and safety of topical treatment with an antibiotic ear drop formulation in comparison to glycerol treatment. Curr Med Res Opin. 2011;27(4):871–8.
15. Emgard P, Hellstrom S. A group III steroid solution without antibiotic components: an effective cure for external otitis. J Laryngol Otol.
2005;119(5):342–7.
16. Lambert I. A comparison of the treatment of otitis externa with‘otos- porin’and aluminium acetate: a report from a services practice in cyprus. J R Coll Gen Pract. 1981;31(226):291–4.
17. Panahi Y, Akhavan A, Sahebkar A, Hosseini S, Taghizadeh M, Akbari H, et al. Investigation of the effectiveness of Syzygium aroma- ticum, Lavandula Angustifolia and Geranium robertianum essential oils in the treatment of acute external otitis: a comparative trial with ciprofloxacin. J Microbiol Immunol Infect. 2014;47(3):211–6.
18. Khalil N, Chaudhry S, Ahmad Z, Amin B, Malik F, Samar S, et al. Com- parison of 10% icthammol glycerine wick and topical steroid- antibiotic ear drops in the treatment of diffuse otitis externa. RMJ.
2019;44(3):637–40.
19. Akshaya T, Nandhini R, Shoba K. Steroid antibiotic pack versus 10% ichthammol glycerol pack in management of acute otitis externa: a comparative study. Int J Res Pharm Sci. 2021;12(1):
192–8.
20. Dadagian AJ, Hicks JJ, Ordonez GE, Glassman JM. Treatment of otitis externa: a controlled bacteriological-clinical evaluation. Curr Ther Res Clin Exp. 1974;16(5):431–6.
21. Amani S, Moeini M. Comparison of boric acid and combination drug of Polymyxin, neomycin and hydrocortisone (polymyxin NH) in the treatment of acute otitis externa. J Clin Diagn Res. 2016;10(7):
MC01-4.
22. Tsikoudas A, Jasser P, England R. Are topical antibiotics necessary in the management of otitis externa? Clin Otolaryngol. 2002;27(4):
260–2.
23. Abelardo E, Pope L, Rajkumar K, Greenwood R, Nunez DA. A double- blind randomised clinical trial of the treatment of otitis externa using
topical steroid alone versus topical steroid-antibiotic therapy. Eur Arch Otorhinolaryngol. 2009;266(1):41–5.
24. Slack R. A study of three preparations in the treatment of otitis externa. J Laryngol Otol. 1987;101(6):533–5.
25. Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhoea. Clin Otolaryngol Allied Sci.
1990;15(1):7–10.
26. National Institute for Health and Care Excellence (NICE). Wound management products and elasticated garments. [cited 2022 Nov 08]. Available from:https://bnf.nice.org.uk/wound-management/
27. Bigliardi PL, Alsagoff SAL, El-Kafrawi HY, Pyon J-K, Wa CTC, Villa MA. Povidone iodine in wound healing: a review of current con- cepts and practices. Int J Surg. 2017;44:260–8.
28. Ordonez G, Kime C, Updegraff W. Effective treatment of acute, dif- fuse otitis externa I a controlled comparison of hydrocortisone-acetic acid, nonaqueous and hydrocortisone-neomycin-polymyxin B otic solutions. Curr Ther Res Clin Exp. 1978;23(5):SS3–14.
29. Nilssen E, Wormald PJ, Oliver S. Glycerol and ichthammol: medici- nal solution or mythical potion? J Laryngol Otol. 1996;110(4):
319–21.
30. Gayko G, Cholcha W, Kietzmann M. Anti-inflammatory, antibacterial and antimycotic effects of dark sulfonated shale oil (ichthammol). Berl Munch Tierarztl Wochenschr. 2000;113(10):368–73.
31. Shrestha B, Shrestha I, Amatya R, Dhakal A. Effective treatment of acute otitis externa: a comparison of steroid antibiotic versus 10%
ichthammol glycerine pack. Indian J Otolaryngol Head Neck Surg.
2010;62(4):350–3.
32. Adhikari P, Bhatta R, Bhandari S, Pyakurel BM. Comparison of steroid antibiotic pack and 10% ichthammol glycerine pack in relieving pain of acute otitis externa in children. Int J Pediatr Otorhinolaryngol.
2011;75(4):500–3.
33. Kabadar P, Doddamani SS, Mathri A. A comparative study of antibiotic-steroid pack with Glycerine pack in treatment of acute oti- tis externa. Indian J Otolaryngol Head Neck Surg. 2022;74:4472–4.
34. Smith ME, Hardman JC, Mehta N, Jones GH, Mandavia R, Anderson C, et al. Acute otitis externa: consensus definition, diagnostic criteria and core outcome set development. PloS One. 2021;16(5):e0251395.
35. National Institute for Health and Care Excellence (NICE). Dexametha- sone with glacial acetic acid and neomycin sulfate. [cited 2022 Nov 08]. Available from: https://bnf.nice.org.uk/drugs/dexamethasone- with-glacial-acetic-acid-and-neomycin-sulfate/
S U P P O R T I N G I N F O R M A T I O N
Additional supporting information can be found online in the Support- ing Information section at the end of this article.
How to cite this article:Di Traglia R, Tudor-Green B, Muzaffar J, Borsetto D, Smith ME. Antibiotics versus non- antibiotic treatments for acute otitis externa: A systematic review and meta-analysis. Clinical Otolaryngology. 2023.
https://doi.org/10.1111/coa.14084
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