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 72/44 (7-84) Rahman et al[16] (1998) Bangla-desh 71 NS NS NS 27/9 25/10 52/19 Rahman et al[17] (1997) India 60 44.3±17.3 42.6±16.2 NS NS NS NS NS: Not specified in RCT; NAT: Natamycin. Table 2 Administration of natamycin in included studies Concentration NAT regimen Completion of follow-up (No. of patients) Study (a) Follow-up of NAT(%) and duration NAT Control Overall Prajna et al[12] (2013) 3mo 5 once/2h for 3mo 141/162 143/161 284/323 Arora et al[11] (2011) 2mo 5 once/h for 2mo 15/15 15/15 30/30 Prajna et al[13] (2010) 3mo 5 once/2h for 3mo 56/60 53/60 109/120 Wang et al[14] (2010) 35d 5 7 times/d for 35d 42/42 42/42 84/84 Prajna et al[15] (2003) 1mo 5 once/2h for 1mo 59/61 52/55 111/116 Rahman et al[16] (1998) 21d 2.5 once/3h for 21d 27/36 26/35 53/71 Rahman et al[17] (1997) 21d 5 once/3h for 21d 16/18 42/42 58/60
Figure1Flowdiagramofselectionprocessofarticlesforthis Meta-analysis.
2.5%natamycin [16].Natamycinregimenanddurationwere almostlyoncefor2hor3h,only1trialusingnatamycin7 timesperday [14].Allthedurationswereuptothefollow-up time(Tables1,2). QuantitativeDataSynthesis Riskofbiasinincludedrandomizedcontrolledtrials Figure2Riskofbias Eachriskofbiasitemforeachselected Figures2and3showtheriskofbiasassessmentonincluded study. 599 Natamycininthetreatmentoffungalkeratitis
Figure3Riskofbias Eachriskofbiaseventpresentedaspercentagesacrossallselectedtrials.
Figure4Comparisonoftheresponseofchlorhexidinegluconateandnatamycininmanagementoffungalkeratitisatfivedays.
Figure5Comparisonoftheeffectofchlorhexidinegluconateandnatamycininmanagementoffungalkeratitisoncornealulcer healedat21d. trials.Forselectionbias,4trials [12,13,16,17] of7RCTsreported healingoftheulcerat21dwaslessconclusive(RR=0.77, adequatemethodsofsequencegenerationandallocation 95%CI,0.55to1.08; 2 =0%;Figure5) [16,17].Instudiesof concealment. Itwas always difficult for maskingof Arora [11] andPrajna [12,13] therewerenoevidence participants.Forperformanceanddetectionbiases,only2 foranydifferencebetweennatamycinandvoriconazole. studies [12,13] reportedadequatemaskingofparticipants, However,thestudyofArora [11] wasrathersmallandit personnelandoutcomeassessment.Forattritionbias,5 wasimpossibletocombinethedataofthesestudiesbecause trials [11-14,17] of7hadreasonablycompletedataandwere ofdifferencesinoutcomespresented.In2010,Prajna [13] judgedaslowrisk.Intheotherstudies,attritionbiaswas foundthatpeopletreatedwithvoriconazolehada1line consideredtobepossible.Intheincludedtrials,reporting betterbestcorrectvisualacuitycomparedtopeopletreated biaswasnotconsideredtobeamajorproblembutitwas withnatamycinatthreemonths,however,thisdifference alwaysdifficulttoevaluateitsufficiently. wasnotstatisticallysignificant( =0.29).Otherwise,Prajna OutcomeMeasures Seventrialsreportedthecomparison [12] conductedanothertrialtocomparenatamycinwith ofnatamycintodifferentantifungalagents.Prajna [15] voriconazolein2013,suggestingthatnatamycintreatment showedthattherewerelittledifferenceintheeffectsof appearedtobe significantlybetterclinicaland econazoleandnatamycinwhichwaspublishedin2003 microbiologicaloutcomesthanvoriconazoleinmanagement (RR=0.99,95%CI,0.8to1.21).Twoofseventrialscarried offungalkeratitis (regressioncoefficient=-0.18logMAR; outbythesameinvestigatorindicatedthattherewassome 95%CI,-0.30to-0.05; =0.006),andmuchofthevariance evidenceforafavourableeffectofchlorhexidinegluconate due to elevatedresultsin cases(regression comparedtonatamycininresponseatfivedays(RR=0.45, coefficient=-0.41logMAR;95%CI,-0.61to-0.20; <0.001). 95%CI,0.13to1.56; 2 =80%;Figure4),theresultson Wang [14] foundthatnatamycinwasmoreeffectivethan
600 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 fluconazoleinthemanagementoffungalkeratitis,andthere review.Theevidencesupportingnatamycinasagold wasasignificantdifferencebetween natamycinand standardforthetreatmentoffungalkeratitisseemedtobe fluconazoleincurerate(2=5.048, <0.05).Additionally, weak.Thereasonswerethatothereffectiveantifungalagents thenatamycingroupwasmoreeffectivethanfluconazolein suchasamphotericinB[7,23,24],itraconazole[25],miconazoleand averageperiodoftherapy( =7.94, <0.01). sliversulphadiazine [26-28] havenotyetbeencomparedina Prajna [12] concludedthatnatamycin-treatedcaseshad largescaleRCTs,andthetrialscomparednatamycinto lesslikelytohaveperforationorrequiretherapeutic differentantifungalagentswithdifferentoutcomemeasures. penetratingkeratoplastythanvoriconazole-treatedcasesin Soitwasinadvisabletoputthedatatogether,andwedidnot thestudywhichwaspublishedin2013(OR=0.42;95%CI, poolalltheresultssincetherewasnolargescaletrialfor 0.22to0.80; =0.009),butdidnotdescribetheadverse natamycincomparingtoparticularagent.However,natamycin reactionofdrugsindetails,soastohistwoothertrials [13,15]. hasbeenregardedasthefirstlineinthemanagementof Noadversereactionstostudyantifungalagentswerenoted fungalkeratitis [29].Afewresearcheshadreportedthat inArora 's [11] trial.Therewasnodescriptionsof natamycinwassignificantlymoreeffectivethanvoriconazole significant systemicorocularadverse reactionsfrom orfluconazoleinmanagementof fungal keratitis. natamycinandchlorhexidinegluconategroups,butacaseof Participantsexposedtonatamycinhadpreferable3mo temporarypunctateepitheliopathywasreportedinone BSCVAorhighercurerate,particularlyin cases. patientreceivingchlorhexidinegluconateduetofrequent Inadditiontoconventionalrouteofadministration,suchas applicationofthedrops [16,17].Noearlycataractformationfor localeyedrops,oral,intravenousinjection,eyeointment, participants treated with chlorhexidinegluconateand therehasbeensubconjunctivalinjectionandinjectionin natamycinwasrecordedatsixmonthstooneyearafter cornealstromafortreatingfungalkeratitis.Themain treatment.Therewerenosystematicmildsideeffects treatmentoffungalkeratitisisusingantifungaleyedrops. observedinthetrialofWang [14] whichcompared Systematicuseofagentspossessesserioussideeffects. natamycintofluconazole. Natamycinpoorlypenetratesintotheaqueousandisunable DISCUSSION toachievetherapeuticlevelsbyintravenousinjectionand Meta-analysisattemptstoanalyzeandcombinetheresultsof subconjunctivalinjection.Cultureandsensitivityresultsplay previousreports [18].Thissystematicreviewprovidedacritical avitalroleforconductingmedicaltherapyforinfectious overviewofpreviousclinicalreportsandcombinedeffect diseases,butfungigrowslowerthanotherpathogens [30]. measuresofnatamycininmultiplesmallclinicaltrialsto Therefore,weneedtoapplyantifungaldrugsassoonas increasestatisticalpower.Itincludedseventrialscomparing discoveringfungalelementsontheexaminationsuchas natamycintodifferentantifungaldrugsforthetreatmentof smear,confocalmicroscopyandsoon [31-33].Soweneedto fungalkeratitis.Alltrialswereimplementedindeveloping findamoreeffectiveagenttobeadministeredintheearly countriesbecauseofthehigherincidencethandeveloped periodoffungalkeratitis.However,thedrugsusedinthe countries.Therearestillnolargemulticentrerandomised currentRCTsweredifferent,andtheevidencethatverified trialstoassesstheefficacyofnatamycinonthetreatmentof whichagentwasmoreeffectiveforfungalkeratitiswasweak fungalkeratitis. duetothesmallsamplesize.Inourreview,wefoundthat Fourantifungalagents,namely,voriconazole,econazole, natamycinwasusefulthansomeotherantifungalagentslike fluconazoleandchlorhexidinegluconatewerecomparingto voriconazole andfluconazole.Sowerecommendthat natamycin.Formerthreedrugsareconventionalagentsfor natamycinismorefavorableapplyingintheearlyperiodof fungalinfection.Theyaretriazolesandactbyinhibitingthe fungalkeratitis. biosynthesisofergosterol,whichnatamycinbindswith. Insummary,natamycinwasapreferablechoiceinthe Natamycinhasbeenconsideredtobemainstayfortreatment treatmentoffungalkeratitis,especiallyinthe offilamentousfungalkeratitis [19].Natamycinistheonly cases.Importantly,furtherRCTswithlargesamplesizeare commercialantifungaldruginophthalmicformandis neededandthesearchformoreeffectiveandcheaper expensive [9,20,21].Sincefungalkeratitisoftenoccursin interventionsforfungalkeratitiswouldbenecessary. developingcountries,natamycinperformslimitedavailability ACKNOWLEDGEMENTS althoughnatamycinisofferedasaservicedrug [22].There Foundations: SupportedbyNationalNaturalScience wereafewclinicaltrialshavebeendoneonnatamycinto FoundationofChina(No.81170825;No.81470609); evaluatetheefficacybycomparingtootheragents. ShandongProvinceNaturalScienceFoundation(No. Thereisnosignificantevidencesuggestingthatnatamycinis ZR2013HQ007;No.ZR2012HZ001);theSpecialized moreeffectivethanotherantifungalagentsforthetreatment ResearchFundfortheDoctoralProgramofHigherEducation, offungalkeratitisintermsoftheseventrialsincludedinthis 2012(No.20123706110003). 601 Natamycininthetreatmentoffungalkeratitis ConflictsofInterest:QiuS, None; ZhaoGQ, None; Lin Trialofchlorhexidinegluconateforfungalcornealulcers. J, None; WangX, None; HuLT, None; DuZD, None; 1997;4(3):141-149 WangQ, None; ZhuCC, None. 18SacksHS,BerrierJ,ReitmanD,Ancona-BerkVA,ChalmersTC. 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