Antimicrobial drugs for treating cholera - LSTM Online Archive

100 Pages·2014·0.87 MB·English

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
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ollabo2014ialdru Antimicrobialdrugsversusplacebo/notreatmentfortreatingcholera
rationTheAgsfor Patientorpopulation:Adultsandchildrenwithcholeradiarrhoea
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eCole Outcomes Illustrativecomparativerisks*(95%CI) Relativeeffect Noofparticipants Qualityoftheevidence Comments
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Sy Diarrhoeaduration Themeandurationofdi- Themeandurationofdi- 1013 ⊕⊕⊕(cid:13)
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te arrhoea in the control arrhoeaintheintervention (19studies) moderate
m
a groupsrangedfrom groupswas 1,2,3,4
ticR 29.3to127.2hours 36.77hoursshorter
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v (43.51 to 30.03 hours
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lish Stoolvolume The median volume The corresponding vol- ROM0.50(0.45to0.56) 1042 ⊕⊕⊕(cid:13)
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d across control groups ume with antibiotics (18studies) moderate1,2,3,4
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y was13.5litresforadults would be 7.3 litres for
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.o was 14 litres for adults would be 8.4 litres for
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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
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ste Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
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tic Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.
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sp 1 Downgradedby1forriskofbias:inasensitivityanalysisrestrictedtothefewtrialsatlowriskofselectionbiastheeffectsizewas
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he 2Noseriousinconsistency:statisticalheterogeneitywashigh,howeverthisrelatedtothesizeoftheeffectseenwithdifferentantibiotics.
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Jo 3Noseriousindirectness:althoughmanyofthetrialsarenowold,anddrugsusceptibilitypatternshavechanged,theseresultsarelikely
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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.