Antimicrobial drugs for treating cholera (Review) Leibovici-WeissmanY, Neuberger A, Bitterman R, SinclairD, Salam MA, Paul M ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary 2014,Issue6 http://www.thecochranelibrary.com Antimicrobialdrugsfortreatingcholera(Review) Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 18 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 98 Antimicrobialdrugsfortreatingcholera(Review) i Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. [InterventionReview] Antimicrobial drugs for treating cholera Ya’araLeibovici-Weissman1,AmiNeuberger2,RoniBitterman2,DavidSinclair3,MohammedAbdusSalam4,MicalPaul5 1SacklerFacultyofMedicine,TelAviv,Israel.2DivisionofInfectiousDiseases,RambamHealthCareCampusandTheRuthandBruce RappaportFacultyofMedicine,Technion-IsraelInstituteofTechnology,TelAviv,Israel.3DepartmentofClinicalSciences,Liverpool SchoolofTropicalMedicine,Liverpool,UK.4Research&ClinicalAdministrationandStrategy,InternationalCentreforDiarrhoeal DiseaseResearch,Bangladesh(ICDDR,B),Dhaka,Bangladesh.5DivisionofInfectiousDiseases,RambamHealthCareCampusand theTechnion-IsraelInstituteofTechnology,Haifa,Israel Contact address: Ya’ara Leibovici-Weissman, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 49100, Israel. [email protected]. Editorialgroup:CochraneInfectiousDiseasesGroup. Publicationstatusanddate:New,publishedinIssue6,2014. Reviewcontentassessedasup-to-date: 30March2014. Citation: Leibovici-WeissmanY,NeubergerA,BittermanR,SinclairD,SalamMA,PaulM.Antimicrobialdrugsfortreatingcholera. CochraneDatabaseofSystematicReviews2014,Issue6.Art.No.:CD008625.DOI:10.1002/14651858.CD008625.pub2. Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfof TheCochraneCollaboration.ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-Non-Commercial Licence,whichpermitsuse,distributionandreproductioninanymedium,providedtheoriginalworkisproperlycitedandisnotused forcommercialpurposes. ABSTRACT Background CholeraisanacutewaterydiarrhoeacausedbyinfectionwiththebacteriumVibriocholerae,whichifseverecancauserapiddehydration anddeath.Effectivemanagementrequiresearlydiagnosis andrehydrationusing oralrehydrationsaltsorintravenous fluids.Inthis review,weevaluatetheadditionalbenefitsoftreatingcholerawithantimicrobialdrugs. Objectives Toquantifythebenefitofantimicrobialtreatmentforpatientswithcholera,anddeterminewhethertherearedifferencesbetweenclasses ofantimicrobialsordosingschedules. Searchmethods WesearchedtheCochraneInfectiousDiseaseGroupSpecializedRegister;theCochraneCentralRegisterofControlledTrials(CEN- TRAL);PubMed;EMBASE;AfricanIndexMedicus;LILACS;ScienceCitationIndex;metaRegisterofControlledTrials;WHOIn- ternationalClinicalTrialsRegistryPlatform;conferenceproceedings;andreferenceliststoMarch2014. Selectioncriteria Randomizedandquasi-randomizedcontrolledclinicaltrialsinadultsandchildrenwithcholerathatcompared:1)anyantimicrobial treatmentwithplaceboornotreatment;2)differentantimicrobialshead-to-head;or3)differentdosingschedulesordifferentdurations oftreatmentwiththesameantimicrobial. Datacollectionandanalysis Two reviewers independently applied inclusion and exclusion criteria, and extracted data from included trials. Diarrhoea duration andstoolvolumeweredefinedasprimaryoutcomes.Wecalculatedmeandifference(MD)orratioofmeans(ROM)forcontinuous outcomes, with 95%confidence intervals(CI),andpooleddatausing arandom-effectsmeta-analysis. Thequality ofevidence was assessedusingtheGRADEapproach. Antimicrobialdrugsfortreatingcholera(Review) 1 Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. Mainresults Thirty-ninetrialswereincludedinthisreviewwith4623participants. Antimicrobialsversusplaceboornotreatment Overall,antimicrobialtherapyshortenedthemeandurationofdiarrhoeabyaboutadayandahalfcomparedtoplaceboornotreatment (MD -36.77 hours, 95% CI -43.51 to -30.03, 19 trials, 1013 participants, moderate quality evidence). Antimicrobial therapy also reducedthetotalstoolvolumeby50%(ROM0.5,95%CI0.45to0.56,18trials,1042participants,moderatequalityevidence)and reducedtheamountofrehydrationfluidsrequiredby40%(ROM0.60,95%CI0.53to0.68,11trials,1201participants,moderate qualityevidence).Themeandurationoffecalexcretionofvibrioswasreducedbyalmostthreedays(MD2.74days,95%CI-3.07to- 2.40,12trials,740participants,moderatequalityevidence). Therewassubstantialheterogeneityinthesizeofthesebenefits,probablyduetodifferencesintheantibioticused,thetrialmethods (particularly effective randomization), and the timing of outcome assessment. The benefits of antibiotics were seen both in trials recruitingonlypatientswithseveredehydrationandinthoserecruitingpatientswithmixedlevelsofdehydration. Comparisonsofantimicrobials Inhead-to-headcomparisons,therewerenodifferencesdetectedindiarrhoeadurationorstoolvolumefortetracyclinecomparedto doxycycline(threetrials,230participants,verylowqualityevidence);ortetracyclinecomparedtociprofloxacinornorfloxacin(three trials,259participants,moderatequalityevidence).Inindirectcomparisonswithsubstantiallymoretrials,tetracyclineappearedtohave largerbenefitsthandoxycycline,norfloxacinandtrimethoprim-sulfamethoxazolefortheprimaryreviewoutcomes. Singledoseazithromycinshortenedthedurationofdiarrhoeabyoveradaycomparedtociprofloxacin(MD-32.43,95%CI-62.90 to-1.95,twotrials,375participants,moderatequalityevidence)andbyhalfadaycomparedtoerythromycin(MD-12.05,95%CI- 22.02to-2.08,twotrials,179participants,moderatequalityevidence).Itwasnotcomparedwithtetracycline. Authors’conclusions Intreating cholera,antimicrobials resultinsubstantial improvementsinclinicaland microbiological outcomes, with similar effects observedinseverelyandnon-severelyillpatients.Azithromycinandtetracyclinemayhavesomeadvantagesoverotherantibiotics. PLAIN LANGUAGE SUMMARY Antibioticsfortreatingcholera CochraneCollaborationresearchersconductedareviewoftheeffectsofantibioticsfortreatingpeoplewithcholera.Aftersearchingfor relevanttrials,theyincluded39randomizedcontrolledtrialsenrolling4623peoplewithcholera. Whatischoleraandhowmightantibioticswork Choleraisaformofseverewatery diarrhoea,whichspreadsfrompersontopersonthroughfoodandwatercontaminated withthe bacteriumVibriocholerae.Choleraiscommoninplaceswithpoorwaterandsanitation, andsometimescauseslargeepidemicswith thousandsofpeoplefallingill. Choleracancauseseveredehydrationanddeath,sothemaintreatmentistogivefluidsandsalteitherorallyasoralrehydrationsalts,or byinjection.Byclearingthebacteriaearlierthanthepatientsownimmunesystem,antibioticscouldreducethedurationandseverity oftheillness,andreduceonwardtransmissiontootherpeople. Whattheresearchsays Antibiotictreatmentshortenedthedurationofdiarrhoeabyaboutoneandahalfdays(thenormaldurationisbetweenthreeandfour days),andreducedthetotalamountofdiarrhoeafluidbyhalf.Consequently,theneedforrehydrationfluidswasalsoreducedbyalmost half. Antibiotictreatmentalsoshortenedtheperiodoftimewherethepatientremainscontagiousbyreducingthedurationofexcretionof Vibriocholeraeinthediarrhoea. Thebenefitsofantibioticswereseenintrialsrecruitingonlypeoplewithseveredehydration,andinthoserecruitingpeoplewithmixed levelsofdehydration. Antimicrobialdrugsfortreatingcholera(Review) 2 Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. Tetracyclineorazithromycinappearmoreeffectivethansomeoftheotherantibioticstested,butthechoiceofwhichantibiotictouse willdependonlocaldrugresistance. Antimicrobialdrugsfortreatingcholera(Review) 3 Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. CoCoAn SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation] chranepyrighttimicro C©b ollabo2014ialdru Antimicrobialdrugsversusplacebo/notreatmentfortreatingcholera rationTheAgsfor Patientorpopulation:Adultsandchildrenwithcholeradiarrhoea .uthors.treating ICnotemrpvaernitsioonn::APlnatcimebicor/onboiatlredartumgesnt Tc hh eCole Outcomes Illustrativecomparativerisks*(95%CI) Relativeeffect Noofparticipants Qualityoftheevidence Comments ocra (95%CI) (studies) (GRADE) hra(Re nv eie Assumedrisk Correspondingrisk Dw a) ta ba Placebo/notreatment Antimicrobialdrugs s e o f Sy Diarrhoeaduration Themeandurationofdi- Themeandurationofdi- 1013 ⊕⊕⊕(cid:13) s te arrhoea in the control arrhoeaintheintervention (19studies) moderate m a groupsrangedfrom groupswas 1,2,3,4 ticR 29.3to127.2hours 36.77hoursshorter e v (43.51 to 30.03 hours ie ws shorter) p u b lish Stoolvolume The median volume The corresponding vol- ROM0.50(0.45to0.56) 1042 ⊕⊕⊕(cid:13) e d across control groups ume with antibiotics (18studies) moderate1,2,3,4 b y was13.5litresforadults would be 7.3 litres for Jo hn and 368 ml/kg for chil- adults(6.1to7.6L),and W dren 184 mL/kg for children iley (166to206mL/kg) & S o ns Hydration fluid require- The median volume The corresponding vol- ROM0.60 1201 ⊕⊕⊕(cid:13) , Ltd ments across control groups ume with antibiotics (0.53to0.68) (11studies) moderate1,2,3,4 .o was 14 litres for adults would be 8.4 litres for n b and 374 mL/kg for chil- adults(7.4to9.5L),and e h a dren 224 mL/kg for children lf o (198to254mL/kg) f T h e 4 CCA oon chraneCpyright©timicrob Durationofpathogense- The mean duration of The mean duration of 740 ⊕⊕⊕(cid:13) ollabo2014ialdru cretion pcoatnhtoroglengsreocurpestionrainngthede pinatethrovegnetniosnecgrreotiuopnsinwthaes (12studies) moderate5,2,3,4 ration.TheAuthors.gsfortreating f2r.o9m7to6.0days 2s(3h.7.o04r7tedra)ytsosh2o.r4te0r days Tc heho Deaths - - Seecomment 299 - No deaths occurred in Cle ocra (7studies) thesestudies hra(Re nv eie *Thebasisfortheassumedrisk(egthemediancontrolgroupriskacrossstudies)isprovidedinfootnotes. Thecorrespondingrisk(andits95%CI)isbasedontheassumedriskinthe Dw a) comparisongroupandtherelativeeffectoftheintervention(andits95%CI). ta b CI:Confidenceinterval;RR:Riskratio;ROM:Ratioofmeans. a s e o f S GRADEWorkingGroupgradesofevidence y ste Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect. m a Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate. tic Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate. R ev Verylowquality:Weareveryuncertainabouttheestimate. ie w sp 1 Downgradedby1forriskofbias:inasensitivityanalysisrestrictedtothefewtrialsatlowriskofselectionbiastheeffectsizewas u blis smallerbutremainedstatisticallysignificant. he 2Noseriousinconsistency:statisticalheterogeneitywashigh,howeverthisrelatedtothesizeoftheeffectseenwithdifferentantibiotics. d b Formeta-analysiswithinindividualantibioticsstatisticalheterogeneitywaslow. y Jo 3Noseriousindirectness:althoughmanyofthetrialsarenowold,anddrugsusceptibilitypatternshavechanged,theseresultsarelikely h n W toapplytotreatmentwithantibioticstowhichthecurrentV.choleraeisolatesaresusceptible. ile 4Noseriousimprecision:bothlimitsofthe95%CIrepresentstatisticallysignificantandclinicallyimportanteffects. y & 5Downgradedby1forseriousriskofbias:onlyonestudywasatlowriskofselectionbias. S o n s , L td . o n b e h a lf o f T h e 5 BACKGROUND maining10%ofcasesarelabelledasseverecholera.Mortalityfrom choleradepends on several factors, but is generally preventable. The overall case fatality reportedby the World Health Organi- Descriptionofthecondition zation (WHO)in 2008 was 2.7%, ranging from0% to14.3% indifferentcountries(WHO2009a).Thereportedmortalityin CholeraisanacutewaterydiarrhoeacausedbytheGram-negative Haitihasbeenashighas4.6%insomeareas,butlaterdecreased bacteriumVibriocholera.TherearemanyserogroupsofV.cholerae, to1%orlessthroughoutthecountry(Barzilay2013). ofwhichO1andO139causediseaseinhumans.V.choleraelives Successfulmanagementofcholeradependsonearlydiagnosisand inaquaticenvironments, whereitcansurviveforyearsinafree preventionofdehydration,orprompttreatmentofdehydration livingcycle(Alam2007).Itcausesendemicdiseaseinsomecoun- ifitdevelops.Mildtomoderatedehydrationcanbetreatedwith triesandregions,butithasthepotentialtocauseepidemics(af- Oral Rehydration Salts (ORS) solution, but severe dehydration fectingalargenumberofindividualswithinthepopulation)and usuallyrequiresintravenous(IV)fluids. pandemics(occurringoverawidegeographicareaandaffectingan exceptionallyhighproportionofthepopulation).Childrenaged betweentwoand15areathighestriskinendemicsettings,while Descriptionoftheintervention personsofallagesareaffectedduringepidemics(Glass1982;Sack 2004). Theinterventionassessedinthisreviewistheimpactofantimi- Theincidenceofcholerahasbeenincreasinggloballysincethebe- crobial treatment as an adjunct to rehydration therapy. In the- ginningofthemillennium,witha24%increaseinthenumberof ory,antimicrobialswillnothaveanimmediateeffect,becausethe casesreportedfortheyears2004to2008ascomparedtotheyears toxin is already bound to intestinal cells.However, they should 2000to2004(WHO2009a).However,thetotalof190,130cases affectthedurationofthediseasebyreducingfurtherproduction reportedin2008isconsideredtobeagrossunderestimate,because ofthetoxin,eitherbyinhibitingbacterialproteinsynthesis(tetra- manyendemiccountriesdonotreportcholeraandthisfigurealso cyclines,macrolides)and/orbypromotingbacterialcelldeath. excludestheestimated500,000to700,000caseslabelledasacute Shorteningthedurationofviablepathogenexcretionmightalso waterydiarrhoeathatoccurinsomeAsianandAfricancountries leadtoreducedtransmission ofinfection toothersandreduced (WHO2009a).Today,themainaffectedregionsworldwide are contaminationoftheenvironment. inAsia(Bangladesh, India, Thailand,Cambodia, andVietnam) TheWHOrecommendsantimicrobialtherapyonlyintheman- andmanypartsofAfrica(includingarecentoutbreakdescribed agementofseverecases,iethosewhoneedintravenousrehydra- inZimbabwe)(Chambers2009;Mintz2009;Sack2004;WHO tionbecauseofseveredehydration;patientswhoarelethargicor 2009b).More recently,the Haiti outbreak spread cholerato the floppy,unconscious,orunabletodrinkORS;orarechildrenwith neighbouringDominicanRepublic,aswellastoCubaandMexico an absence of tears and very slow return of skin pinch (WHO (MinistryofPublicHealthandPopulation2010;Moore2014). 2004). Thecurrent recommendedtreatmentfor adults isasin- V. cholerae is transmitted to humans by the fecal-oral route, gle oral dose of doxycyline 300 mg or tetracycline 12.5 mg/kg through ingestion of contaminated water or food (Zuckerman sixhourlyforthreedays(WHO;Seas1996).Inchildrenunder 2007).Forexample,onehypothesissuggeststhatV.choleraewas eightyearsofage,co-trimoxazole,erythromycinorazithromycin introducedintoHaitibyinfectedNepalesepeacekeepingsoldiers arerecommended(WHO). and that the epidemic spread of the organism was due to poor Thechoiceofantimicrobialagentiscomplicatedbyemergingre- sanitation (Ceccarelli2011;Frerichs2012).The incubation pe- sistancetoantibiotics.Resistancetotetracyclineemergedin1979, riodforcholerausuallyvariesbetweeneightto72hours,depend- followedbyresistancetootherantibioticclasses(Mhalu1979).A ing on the infectious dose and gastric acidity (WHO 2001). V. ’creeping’increaseinminimalinhibitoryconcentrations(MICs) choleraeO1andO139bothcauseclinicaldiseasebysecretingan toquinoloneshasbeennotedsincethe1980s,mediatedbychro- enterotoxinwithasub-unitstructurecomprisingfiveBsubunits mosomalmutations.Tetracyclineresistance,ontheotherhand,is andoneAsubunit(De1959;Dutta1959).TheBsubunitsbind plasmidmediatedandthusMICstotetracyclinedonotincrease thetoxintoaspecificreceptor(GM1ganglioside)onthesurface gradually. In endemic countries, most strains of V. cholerae are oftheintestinalmucosalcells.TheAsubunitisthenreleasedinto currently resistant to co-trimoxazole, with variable resistance to thecellwhereitactivatesadenylatecyclase,causinganetincrease tetracyclines,macrolidesandquinolones(Harris2012).Thus,se- incyclicadenosinemonophosphate,whichblockstheabsorption lectionofantibiotictreatmentshouldbedirectedbytheresultsof ofsodiumbythevillouscells.Thisleadstosecretionofchlorideby antibioticsusceptibilitytestingofV.choleraeisolatesattheonset thecryptcells,followedbysecretionofwater,resultinginwatery ofanoutbreak. diarrhoea. In endemic settings, about 90% of cholera cases are definedasmildtomoderateandareclinicallyimpossibletodis- tinguishfromotheracutewaterydiarrhoeassuchasthosecaused Whyitisimportanttodothisreview byenterotoxigenicEscherichiacoli(ETEC)androtavirus.There- Antimicrobialdrugsfortreatingcholera(Review) 6 Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. Cholera epidemics continue to cause significant morbidity and aseparateanalysisofthosepatientswithprovencholera.Inthis mortalityinmanydevelopingcountriesaroundtheworld.InOc- case,weonlyextracteddataforprovencholeracases. tober 2010, an epidemic of cholera started in Haiti and later spread to the neighbouring Dominican Republic. By October 2012,604,635casesand7436fatalitieshadbeenreportedbythe Typesofinterventions HaitianNationalCholeraSurveillanceSystem(Barzilay2013). • Anyantimicrobialtreatmentversusplacebo/notreatment. Manyrandomized,controlledclinicaltrialshavebeenconducted • Anyantimicrobialversusadifferentantimicrobial. toevaluatetheefficacyofvariousantimicrobial agentsfortreat- • Differentdosingordurationsofthesameantimicrobials. ingcholera.Basedontheresultsofthesetrials,thereisageneral consensus thatantimicrobial treatmentshortenstheduration of Weexcludedantibioticsthatarenotincurrentclinicaluse,such diarrhoeaandreducesstoolvolume(Sack2004;Seas1996).How- as streptomycin, paromomycin, formosulphathiazole, formosul- ever,nosystematicreviewhaspreviouslysummarizedtheevidence phacetamide,andsulfaguanidine. toquantifythebenefitofantimicrobialtreatmentwithregardto Inouranalyses,wedidnotincludetreatmentarmsinwhichover theseoutcomes. 90%oftheV.choleraeisolateswereresistanttothetestedantimi- WiththelatestepidemicofcholerainHaitiinmind,webelieve crobial. thatthereisplaceforasystematicreviewthatwouldhelpanswer thefollowingquestions:towhatextentdoantimicrobialsshorten thecourseoftheclinicaldisease,reducestoolvolumeandtheneed Typesofoutcomemeasures forIVororalhydration;whethercertainantimicrobialsorclasses ofantimicrobialaremoreeffectivethanothersattreatingcholera; andwhatistheoptimaltreatmentschedule. Primaryoutcomes • Durationofdiarrhoea:fromthetimeofinitiationofthe studydruguntiltheendofdiarrhoeaasdefinedinthestudy. OBJECTIVES • Stoolvolume:fromthetimeofinitiationofthestudydrug untilendofdiarrhoeaasdefinedinthestudy. • Toquantifythebenefitofantimicrobialtreatmentfor patientswithcholera. Secondaryoutcomes • Todeterminewhetherdifferentantimicrobialshave • All-causedeaths(’deaths’thereafter)duringtheacute differenteffects. diseasestage(iebeforeresolutionofdiarrhoea). • Todeterminewhetherdifferentlengthsoftreatmentor • Durationoffecalexcretionofthepathogen. dosingofantimicrobialshavedifferenteffects. • Clinicalfailure:definedaspersistenceofwaterystools beyond48hoursofinitiationofthestudydrug.Whenthis outcomewasreportedatvarioustimepoints,wechosethelast METHODS timepointreported. • Bacteriologicalfailure:definedasisolationofV.cholerae fromstoolsbeyond48hoursofinitiationofthestudydrug. Criteriaforconsideringstudiesforthisreview Whenthisoutcomewasreportedatvarioustimepoints,we chosethelasttimepointreported. • Hydrationrequirements:definedasthetotalvolumeofIV Typesofstudies fluidadministered.Ifnotreported,weuseddataonthetotal volumeofrehydrationfluidadministered,andwhenthatwas Randomizedcontrolledclinicaltrialsorquasi-randomizedstudies notreported,weusedthetotalvolumeofORSadministered. (using alternation, date of birth, patient identification number, weekday). Alloutcome definitions, including the time points defining the outcome (such as schedule and frequency of monitoring), were Typesofparticipants recorded. PatientswithdiarrhoeacausedbyV.choleraeO1orO139,regard- Weintendedtoassessunscheduleduse ofIVrehydration,body less of their age and location of management (ie in-hospital or weightchange, developmentof severe hypokalaemia, severehy- ambulatory). Weincludedtrialsthatrecruitedparticipants with ponatraemiaandresistancedevelopment,buttheseoutcomeswere undiagnoseddiarrhoea(egwaterydiarrhoea)whentheypresented notreportedinmosttrials. Antimicrobialdrugsfortreatingcholera(Review) 7 Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration. Searchmethodsforidentificationofstudies Datacollectionandanalysis Acomprehensivesearchwasconductedwiththepurposeofiden- tifying all eligible trials regardless of language, year of publica- Selectionofstudies tion, or status of publication (published inpeer review journal, Tworeviewersindependentlyappliedinclusionandexclusioncri- conferenceproceeding,thesis,orunpublished).Thelastsearchof teria,andthesearchresultsweredocumentedinanExcelspread- alldatabaseswasconductedinNovember2011andthePubMed sheet. Disagreements were resolved by discussion; if they could searchwasupdatedregularlyuntilMarch2014. notberesolved,weattemptedtocontacttheauthorsofthetrial toclarifyquestionsonitseligibility.Thetrials’reportswerescru- tinized to ensure that multiplepublications fromthesame trial Electronicsearches wereincludedonlyonce.Werecordeddetailsofpotentiallyrele- WeusedthesearchstrategyexplainedinTable1.Thesearchpur- vantreferencesthatwereexcluded,alongwiththereasonfortheir posefullydidnotincludetermsrelatedtotheinterventionbecause exclusion. including theterm’antimicrobial’ wouldpreventtheidentifica- tion of trials that provided only the name of the antimicrobial Dataextractionandmanagement withoutusing’antimicrobial’asanIndexorMeSHterm.Listing allantimicrobialnameswasnotpossiblesincewewerenotaware A data extraction form in Excel was developed, piloted and fi- of all types of antimicrobials that could have been assessed. In nalized.Tworeviewersindependentlyextractedthedatafromin- PubMedandEMBASE,searchtermswereusedincombination cludedtrialsintotheform.Anydisagreementsonextracteddata withthesearchstrategyforretrievingrandomizedcontrolledtrials wereresolvedbydiscussion.Ifnoconsensuscouldbereached,the developedbyTheCochraneCollaboration(Lefebvre2011). trial authors were contacted to clarify theissue. In the eventof Wesearchedthefollowingdatabasesforeligibletrials:Cochrane missingorincompletedata,weattemptedtocontactoneormore Infectious Disease Group Specialized Register (CIDG SR); the ofthetrial’sauthorsforclarification. Cochrane Central Register of Controlled Trials (CENTRAL), Weextracteddescriptivedataonthetrials,thepatientsandinfec- publishedinTheCochraneLibrary;PubMed;EMBASE;African tioncharacteristics,includingtheV.choleraeserogroupandbio- IndexMedicus;LILACS;andtheScienceCitationIndex(CSI). type,andresistanceratesoftheV.choleraesp.isolatestotheantimi- We searched the following databases for unpublished or ongo- crobialstested.Fordichotomousdata,weextractedthenumberof ing trials: metaRegister of Controlled Trials (mRCT) and the patientswitheventandthenumberofpatientsassessed.Forcon- WHO International Clinical Trials Registry Platform (http:// tinuousoutcomes,wepreferentiallyextractedmeansandstandard www.who.int/ictrp/en/)forongoingorunpublishedtrials. deviations.Ifreporteddifferently,weconvertedmedianstomeans andcalculatedthevarianceaccordingtothemethodsdescribedby Hozo2005.Standarderrorsandotherdispersionmeasureswere Searchingotherresources convertedtostandarddeviationswherepossible(Higgins2008).If notreportednumerically,outcomeswereextractedfromgraphsor We attempted to contact key persons in agencies and organiza- figurespresentedinthepublications(bycountingpixels).Studies tionsfundingandconducting trialsonthetreatmentofcholera arenamedbyfirstauthor(abbreviated), yearofpublicationand viaemail,usingourlistofidentifiedtrials,andaskediftheywere triallocationusingtheabbreviationslistedinTable2. awareofotherunidentifiedtrials.Thesepersonsandagenciesin- cluded:HeadoftheEpidemicControlPreparednessProgramme (ECPP) at the International Centre for Diarrhoeal Disease Re- Assessmentofriskofbiasinincludedstudies search,Bangladesh(ICDDR,B);DirectoroftheNationalInstitute Tworeviewersindependentlyassessedpotentialbiasesinincluded ofCholeraandEntericDiseases(NICED),Kolkata,India;theAll studiesandextractedthedataintotheelectronictable.Weuseda IndiaInstituteofMedicalSciences(AIIMS),Delhi,India;theUS domain-basedevaluationasrecommendedbytheCochraneHand- NavalMedicalResearchUnit(NAMRU),Jakarta,Indonesia;the book for Systematic Reviews of Interventions (Higgins 2008). Re- NavalMedicalResearchUnit3(NAMRU-3),Cairo,Egypt;Epi- viewerswerenotblindedtotrialauthors, thepublication status centre,Paris,France;andtheInstitutePasteur,Paris,France,and orotherstudycharacteristics.Eachdomainwasassignedalowor itsnetwork.WealsoattemptedtocontactpeopleattheWHO. highriskofbias, usingthedefinitions providedintheCochrane Referencesofallincludedtrialswerescanned. HandbookforSystematicReviewsofInterventions(Higgins2008). Wesearchedtheproceedingsofthefollowingconferences:theIn- Whentherewas insufficient information about theprocess, the terscienceConferenceonAntimicrobialAgentsandChemother- domain was assigned an unclear riskof bias. Thefollowing do- apy (ICAAC); theEuropeanCongress of Clinical Microbiology mainswereassessedforthisreview. andInfectiousDiseases(ECCMID);andtheInfectiousDiseases • Sequencegeneration SocietyofAmerica(IDSA). • Allocationconcealment Antimicrobialdrugsfortreatingcholera(Review) 8 Copyright©2014TheAuthors.TheCochraneDatabaseofSystematicReviewspublishedbyJohnWiley&Sons,Ltd.onbehalfofThe CochraneCollaboration.