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Natamycin in the Treatment of Fungal Keratitis: a Systematic Review and Meta-Analysis

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Natamycin in the Treatment of Fungal Keratitis: a Systematic Review and Meta-Analysis 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 3熏 Jun.18, 圆园15 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 窑InformaticsResearch窑 Natamycininthetreatmentoffungalkeratitis:a systematicreviewandMeta-analysis 1 DepartmentofOphthalmology,MedicalCollege,Qingdao · KEYWORDS: eyeinfection;fungal;natamycin;Meta- University,Qingdao266071,ShandongProvince,China analysis 2DepartmentofOphthalmology,theAffiliatedHospitalof DOI:10.3980/j.issn.2222-3959.2015.03.29 QingdaoUniversity,Qingdao266003,ShandongProvince, China QiuS,ZhaoGQ,LinJ,WangX,HuLT,DuZD,WangQ,ZhuCC. Correspondence to: Gui-QiuZhao. Departmentof Natamycininthetreatmentoffungalkeratitis:asystematicreviewand Ophthalmology,theAffiliatedHospitalofQingdao Meta-analysis. 2015;8(3):597-602 University,Qingdao266003,ShangdongProvince,China. [email protected] INTRODUCTION Received:2014-11-07 Accepted:2015-01-09 ungalkeratitisisaleadingcauseofblindnessincorneal F diseases,whichisrelativelycommoninwarmclimates [1-3] Abstract anddevelopingcountries .Recentreportssuggestthe prevalenceforfungalketatitiswasincreasing [4,5].Astudy ·AIM:Toreviewpublishedclinicalstudiesexaminingthe reportedthatfungalulcersasaseriouspublichealthproblem effectofnatamycininthetreatmentoffungalkeratitis. innorthChina,inwhichthedominatingpathogenwasgenus ·METHODS:WeselectedthepublicationsinCENTRAL, (77.6%),andthesecondcommonpathogenwas [6] MEDLINE, EMBASE, CNKI, and CBM. This study genus (10.8%) .Moreover,bothof systematicallyreviewedpublishedrandomizedcontrolled and weremostlysensitivetonatamycin.Fungal trials(RCTs)thatcomparednatamycintootherantifungal keratitisresultsinseverevisualimpairment,andthe agents,andconductedfeasibleMeta-analysisofefficacy treatmentismoredifficultthanothercornealinfections [7,8]. resultsusingRevman5.2software. Thegoldstandardforthetreatmentoffungalkeratitishas [9,10] ·RESULTS:Weincludedseventrialswhichweremainly notbeenidentified ,andthemainmanagementis antifungalagentsinvolvingtopicantifungaldropssuchas carriedoutindevelopingcountriesofAsia,withfive natamycinandtopicalamphotericinB.Foracutecorneal trialsconducted in India, oneeach in China and perforationandvisualrehabilitation,therapeuticpenetrating Bangladesh.Atotalof804participantswererandomized keratoplastyisneeded. tofollowingcomparisons:2%econazoleversus5% natamycinshowedlittledifferenceintheeffectsof Theantifungalagentsusedfortreatmentoffungalkeratitis treatmentoffungalkeratitis [RR=0.99,95%confidence includethreeclasses:polyenes,triazoles,andechinocandins. interval(CI),0.8to1.21];chlorhexidinegluconateversus Natamycinisatetraenepolyenewhichhasbeenregardedas 5%natamycinindicatedthattheresultsonhealingofthe themostimportantagentinthemanagementoffungal ulcerat21dwaslessconclusive(RR=0.77,95%CI,0.55 keratitis.Itactsbybindingwithergosterol,whichisan to1.08; 2 =0%);1%voriconazoleversus5%natamycin essentialcomponentinfungalcellwall,andblocksfungal suggestedthatnatamycintreatmentappearedtobe growth.Natamycinis theonlyantifungalmedication significantlybetteroutcomesthanvoriconazole(regression approvedbyU.S.FoodandDrugAdministration [11].There coefficient=-0.18logMAR;95%CI,-0.30to-0.05; = werepreviousstudiesreportingtheefficacyofnatamycin 0.006), especially in cases (regression andcomparingitwithotheragentsinmanagementoffungal coefficient=-0.41logMAR;95%CI,-0.61to-0.20; <0.001); keratitis,buttheresultswerenotcompletelyconsistent. natamycin versus fluconazole showed a significant FlorCruz [9] reportedthatthereisnoevidencetodate differenceincurerate( 2=5.048, <0.05)andnatamycin thatanyparticulardrug,orcombinationofdrugs,ismore groupwasmoreeffectivethanfluconazoleinaverage effectiveinthetreatmentoffungalkeratitis.Therefore,a periodoftherapy( =7.94, <0.01). systematicreviewofavailablereportswillconducetothe ·CONCLUSION:Natamycinwasapreferablechoicein evidencebase,andweperformedthisMeta-analysisto thetreatmentoffungalkeratitis,especiallyintheearly assesstheefficacyofnatamycininthetreatmentoffungal periodof cases. keratitis. 597 Natamycininthetreatmentoffungalkeratitis MATERIALSANDMETHODS reachaconsensusamongtheinvestigators.Thefollowing Search Strategy Wesearched thepublicationsin datawerecollectedfromeachstudy:1)publicationdata:the CENTRAL (whichcontainstheCochraneEyesandVision firstauthor'slastname,yearofpublication,countryof GroupTrialsRegister)(TheCochraneLibrary2014,Issue origin;2)characteristicsoftheparticipants:thesetting, 1),Medline,Embase,CNKI (ChinaNationalKnowledge samplesize,gender,age;3)interventions:natamycin,other Infrastructure), CBM (ChineseBiologicalMedicine antifungalagents,doseofmedication,andadministration Database),followingtheCochrane'shighlysensitivesearch route;4)follow-uptime;5)outcomemeasurement:the strategyandusedrelevantkeywordsandmedicalsubject numberofhealedorhealingulcerstreatedwithnatamycinor heading(MeSH)terms,including"natamycinorpimaricin" otheragents,thenumberofotheroutcomesandthe and"eyeinfections,fungal""antifungalagents".Wealso complications. handsearchedthereferencelistsofidentifiedtrialreportsand WeusedReviewManager5.2forMeta-analysis.We casereportsfortofindrelevantarticles.Therewereon calculatedarelativeriskratiofordichotomousdataandthe languagerestrictionsinthesearchfortrials. weightedmeandifferenceforcontinuousdata.Wecalculated TrialSelection Tworeviewers (QiuSandWangX) thepointestimateandconfidenceintervals(CIs)witha95% independentlyscannedthetitlesandabstractstoexcludethe CIforeachresult.Weevaluatedthestatisticalheterogeneity trialswhichwereobviouslynotconformtotheinclusion byCochrane 2 testsandqualifieditbycalculatingthe criteria.Fulltextreportsofthestudiesthatdefinitelyor 2 statistic.Ifsignificantheterogeneitywasobserved possiblymettheinclusioncriteriawereexaminedforfurther betweenstudies( 2>50%),arandom-effectsmodelwasused assessment.Theycrosscheckedintotheresults,and topoolthedata;otherwise,afixed-effectsmodelwasused. determinedthatwhetherthepapershouldbeexcludedor Weconsideredtoconductingasensitivityanalysisby includedbydiscussionorthethirdreviewer.Wealso excludingstudieswhichwereathighriskofbiasinthe contactedwiththeauthorstoperfectourdata. protocol,butthecurrentstudydoesnotincludemanymore Theinclusioncriteriaincluded:1)type InclusionCriteria Meta-analysissoitwasnotdone.Ifpossiblewewilldo of studies:randomizedcontrolledtrials(RCTs)that furthersensitivityanalysis,sothatwecanjudgethe comparedefficacyofnatamycinwithcontrolorother importanceof reviewresultstocrucialdecisionsand antifungaleyedrop;2)typeofparticipants:allagepatients assumptionsthatwehavemadeduringthereview.Data withfungal keratitis diagnosed clinicallyor analysiswillberepeatedwiththefollowingmethods: microbiologically,andweexcludedthepatientsinfectedby exclusionoftrialsathighriskofbias;exclusionof mixedbacteriaandfungi;3)typeofinterventions:we unpublishedstudies;changinginclusioncriteriaofthe considered studiesusing different concentrationsof studies,participants,interventionsoroutcomemeasures; natamycininthetreatmentoffungalkeratitis.Thisincluded reanalyzingthedatausinganotherstatisticalapproach,such placebocontrolledtrialsortrialscomparingnatamycinto asusingarandom-effectsmodelinsteadofafixed-effects otherantifungalagents;4)typeofoutcomemeasures:a) model. primaryoutcomes:bestspectacle-correctedvisualacuity (BSCVA)at3mo;b)secondaryoutcomes:thetimetobe RESULTS Figure1showedtheselectionofeligible definedasahealedorhealingulcer;thesafetyof StudiesSelection medication;complicationincludingscarsize,perforations; studies.Weidentified493articlesthroughprimaryliterature assessmentandpresenceorabsenceoftoxicityafter search.Twohundredandtwelvearticleswereselectedto treatment. screentheabstractandtitles.Afterthat,198articleswere excludedand14potentialrelevantarticleswereobtainedfor AssessmentofRiskofBias Theriskofbiasinthe includedstudieswasassessedinaccordancewithCochrane fulltextreview.Finally,7eligiblestudieswereincludedfor [11-17] handbook.Twoauthors(QiuSandWangX)independently thesystematicreviewandMeta-analysis . assessed theriskbiasofstudiesand resolvedthe Study Characteristics Table1summarizes the disagreementbydiscussion.Eachbiasdomainlistedinthe characteristicofthe7includedstudies.Atotalof804 Cochraneriskofbiastoolwasassessedandgradedas"low patientswith804eyesin7includedtrialswereenrolledin riskofbias","highriskofbias"and"unclear".Weneedto thisreview.Thebaselinecharacteristicsaresummarizedas contacttheauthorsforillustrationofanyparametergraded follows. The countries of participantsweremainly asunclear. developingcountriesinAsia (5inIndia [11-13,15,17],1eachin [14] [16] DataExtractionandAnalysis Tworeviewers(QiuSand China andBangladesh ).Samplesizewasrangefrom WangX)independentlyimplementedthedataextractionthat 30-323eyes.Themeanageofparticipantswas43.49y,and mettheinclusioncriteria.Thefulltextsofselectedtrials 64%weremale.Thefollow-uptimewasrangefrom21dto werereadtodeterminewhethertheycontaineduseful 3mo.Allthetrialstestedtheefficacyofnatamycinby information.Anydisagreementwasresolvedbydiscussionto comparingwithotherantifungaldrugs.Only1studytested 598 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 3熏 Jun.18, 圆园15 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 Table 1 Basic characteristics of included trials Mean age± SD (a) M/F Study (a) Country n NAT Control Overall NAT Control Overall Prajna et al[12] (2013) India 323 NS NS NS NS NS NS Arora et al[11] (2011) India 30 37.93±15.14 48.47±3.53 NS 10/5 11/4 21/9 Prajna et al[13] (2010) India 120 49.8±11.9 47.0±14.5 NS 42/18 37/23 79/41 45.4±15.38 46.7±15.56 Wang et al[14] (2010) China 84 NS 23/19 22/20 NS (20-66) (5-72) 37.0±13.8 Prajna et al[15] (2003) India 116 NS NS NS NS
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