Nicolle Suzanne Bradley Richard Colgan James C Rice Anthony Schaeffer and Thomas M Hooton University of Manitoba Winnipeg Canada University of Michigan Ann Arbor University of Maryland Baltimore University of Texas Galveston Northwestern University ID: 58650
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Received29October2004;accepted2November2004;electronicallypublished4February2005.TheseguidelinesweredevelopedandissuedonbehalfoftheInfectiousDiseasesSocietyofAmericaandhavebeenendorsedbytheAmericanSocietyofNephrologyandtheAmericanGeriatricSociety.Correspondence:Dr.LindsayE.Nicolle,UniversityofManitoba,HealthSciencesCentre,Rm.GG443,820SherbrookSt.,Winnipeg,MBR3A1R9,CanadaClinicalInfectiousDiseases2005;40:643542005bytheInfectiousDiseasesSocietyofAmerica.Allrightsreserved.3Ð7days(A-II). CID2005:40(1March)Nicolleetal.Table1.InfectiousDiseasesSocietyofAmericaUSPublicHealthServiceGradingSystemforrankingrecommendationsinclinicalguidelines. Category,gradeDeÞnition StrengthofrecommendationAGoodevidencetosupportarecommendationforuse;shouldalwaysbeofferedBModerateevidencetosupportarecommendationforuse;shouldgenerallybeofferedCPoorevidencetosupportarecommendation;optionalDModerateevidencetosupportarecommendationagainstuse;shouldgenerallynotbeofferedEGoodevidencetosupportarecommendationagainstuse;shouldneverbeofferedQualityofevidenceIEvidencefrom1properlyrandomized,controlledtrialIIEvidencefrom1well-designedclinicaltrial,withoutrandomization;fromcohortorcase-controlledanalyticstudies(preferablyfrom1center);frommultipletime-series;orfromdramaticresultsfromuncontrolledexperimentsIIIEvidencefromopinionsofrespectedauthorities,basedonclinicalexperience,descriptivestudies,orreportsofexpertcommittees 8.Norecommendationcanbemadeforscreeningforortreatmentofasymptomaticbacteriuriainrenaltransplantorothersolidorgantransplantrecipients(C-III).Thepurposeofthisguidelineistoproviderecommendationsfordiagnosisandtreatmentofasymptomaticbacteriuriainadultpopulations18yearsofage.Therecommendationsweredevelopedonthebasisofareviewofpublishedevidence,withthestrengthoftherecommendationandqualityoftheevidencegradedusingpreviouslydescribedInfectiousDiseasesSocietyofAmerica(IDSA)criteria(table1)[1].Recommendationsarerelevantonlyforthetreatmentofasymptomaticbacteriuriaanddonotaddressprophylaxisforpreventionofsymptomaticorasymptomaticurinaryinfection.Thisguidelineisnotmeanttoreplaceclinicaljudgment.Screeningofasymptomaticsubjectsforbacteriuriaisappro-priateifbacteriuriahasadverseoutcomesthatcanbepreventedbyantimicrobialtherapy[2].Outcomesofinterestareshortterm,suchassymptomaticurinaryinfection(includingbac-teremiawithsepsisorworseningfunctionalstatus),andlongerterm,suchasprogressiontochronickidneydiseaseorhyper-tension,developmentofurinarytractcancer,ordecreaseddu-rationofsurvival.Treatmentofasymptomaticbacteriuriamayitselfbeassociatedwithundesirableoutcomes,includingsub-sequentantimicrobialresistance,adversedrugeffects,andcost.IftreatmentofbacteriuriaisnotbeneÞcial,screeningofasymp-tomaticpopulationstoidentifybacteriuriaisnotindicated,unlessperformedinaresearchstudytofurtherexplorethebiologyorclinicalsigniÞcanceofbacteriuria.Thus,thereare2topicsofinterest:whetherasymptomaticbacteriuriaisas-sociatedwithadverseoutcomes,andwhethertheinterventionsofscreeningandantimicrobialtreatmentimprovetheseÒAsymptomaticbacteriuria,Óorasymptomaticurinaryinfec-tion,isisolationofaspeciÞedquantitativecountofbacteriainanappropriatelycollectedurinespecimenobtainedfromapersonwithoutsymptomsorsignsreferabletourinaryinfection[3].ÒAcuteuncomplicatedurinarytractinfectionÓisasymp-tomaticbladderinfectioncharacterizedbyfrequency,urgency,dysuria,orsuprapubicpaininawomanwithanormalgeni-tourinarytract,anditisassociatedwithbothgeneticandbe-havioraldeterminants[4].ÒAcutenonobstructivepyelone-phritisÓisarenalinfectioncharacterizedbycostovertebralanglepainandtenderness,oftenwithfever;itoccursinthesamepopulationthatexperiencesacuteuncomplicatedurinaryin-fection.ÒComplicatedurinarytractinfection,Ówhichmayin-volveeitherthebladderorkidneys,isasymptomaticurinaryinfectioninindividualswithfunctionalorstructuralabnor-malitiesofthegenitourinarytract[5].Uncomplicatedurinaryinfectionoccursrarelyinmen,andurinaryinfectioninmenisusuallyconsideredcomplicated.AÒrelapseÓisarecurrenturinarytractinfectionaftertherapyresultingfrompersistenceofthepretherapyisolateintheurinarytract.ÒReinfectionÓisrecurrenturinarytractinfectionwithanorganismoriginatingfromoutsideoftheurinarytract,eitheranewbacterialstrainorastrainpreviouslyisolatedthathaspersistedinthecolo-nizingßoraofthegutorvagina[4].ÒPyuriaÓisthepresenceofincreasednumbersofpolymorphonuclearleukocytesintheurineandisevidenceofaninßammatoryresponseintheuri-narytract[6].LITERATUREREVIEWTherecommendationsinthisguidelineweredevelopedafterareviewofstudiespublishedinEnglish.ThesewereidentiÞedthroughasearchofthePubMeddatabasesupplementedby CID2005:40(1March)Nicolleetal.Table2.Prevalenceofasymptomaticbacteriuriainselectedpopulations. PopulationPrevalence,%Reference Healthy,premenopausalwomen1.0Ð5.0[31]Pregnantwomen1.9Ð9.5[31]Postmenopausalwomenaged50Ð70years2.8Ð8.6[31]DiabeticpatientsWomen9.0Ð27[32]Men0.7Ð11[32]ElderlypersonsinthecommunityWomen10.8Ð16[31]Men3.6Ð19[31]Elderlypersonsinalong-termcarefacilityWomen25Ð50[27]Men15Ð40[27]PatientswithspinalcordinjuriesIntermittentcatheteruse23Ð89[33]Sphincterotomyandcondomcatheterinplace57[34]Patientsundergoinghemodialysis28[28]PatientswithindwellingcatheteruseShort-term9Ð23[35]Long-term100[22] 70years.1%amongschoolgirlsto20%amonghealthywomenyearsofagelivinginthecommunity[31].Theprevalenceofbacteriuriaamongyoungwomenisstronglyassociatedwithsexualactivity.Itwas4.6%amongpremenopausalmarriedwomenbutonly0.7%amongnunsofsimilarage[12].Pregnantandnonpregnantwomenhaveasimilarprevalenceofbacte-riuria(2%Ð7%)[31].Bacteriuriaismorecommonindiabeticwomen,withaprevalenceof8%Ð14%,andisusuallycorrelatedwithdurationofdiabetesandpresenceoflong-termcompli-cationsofdiabetes,ratherthanwithmetabolicparametersofdiabeticcontrol[36].Asymptomaticbacteriuriaisrareinhealthyyoungmen[37].Theprevalenceinmenincreasessub-stantiallyaftertheageof60years,presumablybecauseofob-structiveuropathyandvoidingdysfunctionassociatedwithpro-statichypertrophy[27,37].From6%to15%ofmen75yearsofagewhoresideinthecommunityarebacteriuric[31].Di-abeticmendonotappeartohaveanincreasedprevalenceofbacteriuria,comparedwithnondiabeticmen[32].Manypatientgroupswithchronicdisabilitiesorcomorbid-itiescharacterizedbyimpairedurinaryvoidingorwithin-dwellingurinarydeviceshaveaveryhighprevalenceofasymp-tomaticbacteriuria,irrespectiveofsex.Patientswithshort-termindwellingurethralcathetersacquirebacteriuriaattherateof2%Ð7%perday(table2)[35,38].Patientswithspinalcordinjuryhaveaprevalenceof50%,whethervoidingismanagedbyintermittentcatheterizationorbysphincterotomyandcon-domdrainage[33,34].Patientsundergoinghemodialysishaveaprevalenceofasymptomaticbacteriuriaof28%[28].Twenty-Þvepercentto50%ofelderlywomenand15%Ð40%ofelderlymeninlong-termcarefacilitiesarebacteriuric[27].Thema-jorityoftheseelderlypersonshavechronicneurologicillnesses,withthehighestprevalenceofbacteriuriaobservedinthemosthighlyfunctionallyimpairedresidents.Theclinicalassessmentofelderlybacteriuricresidentstoascertainthepresenceorab-senceofsymptomsmaybeproblematic,andobservationsofcloudyorsmellyurinebythemselvesshouldnotbeinterpretedasindicationsofsymptomaticinfection[39].Useofalong-termindwellingcatheter[22]orpermanenturetericstent[40]isassociatedwithbacteriuriavirtually100%ofthetime.MICROBIOLOGYOFASYMPTOMATICEscherichiacoliremainsthesinglemostcommonorganismiso-latedfrombacteriuricwomen[11,12,41],althoughthishap-pensproportionallylessfrequentlythanforwomenwithacuteuncomplicatedurinarytractinfection.E.colistrainsisolatedfromwomenwithasymptomaticbacteriuriaarecharacterizedbyfewervirulencecharacteristicsthanarethoseisolatedfromwomenwithsymptomaticinfection[42].OtherEnterobacter-iaceae(suchasKlebsiellapneumoniae)andotherorganisms(includingcoagulase-negativestaphylococci,Enterococcuscies,groupBstreptococci,andGardnerellavaginalis)arecom-monaswell.Formen,coagulase-negativestaphylococciarealsocommon,inadditiontogram-negativebacilliandEnterococcusspecies[43,44].Subjectswithabnormalitiesofthegenitouri- CID2005:40(1March)Nicolleetal.Table3.Findingsofcomparativeclinicaltrialsofantimicrobialtherapyforthetreatmentofasymptomaticbacteriuriainpregnancy. Reference(s)DesignAntimicrobialtherapyNo.ofpatientswithpyelonephritis/totalno.ofpatients(%) Initiallypositiveresult Treated LeBlancandMcGanity[55]Randomized,notblindedSulfonamideandmandelamine,nitro-furantoin,ormandelaminealone;mandelaminetoterm22/1143(1.9)3/69(4.3)8/41(20)BrumÞt[56]andCondieetal.[57]Randomized,placebo-controlledSulfonamides3/150(2)4/67(6.0)55/179(31)Wren[58]AlternatingbetweenantibioticsandnoantibioticsNitrofurantoin,ampicillin,sulfonamide,andnalidixicacidtotermÉNS33/90(37)Elderetal.[59]Alternating,placebo-controlledTetracyclinefor6weeks6/279(2)4/133(3.0)27/148(18)Savageetal.[52]Alternating,placebo-controlledSulfonamidetoterm7/496(1.4)1/93(1.1)26/98(26)Kincaid-SmithandBullen[26]Cohort,sequentialVariousÉ2/61(3.3)20/53(37)Little[54]Randomized,notblindedSulfonamidetoterm19/4735(0.4)4/124(3.2)35/141(25) NS,notspeciÞed.Microbiologicresultsfrominitialscreeningurinecultureinpregnancy.mentofasymptomaticbacteriuriaduringpregnancy,admin-istrationofantimicrobialtherapyusuallycontinuedforthedurationofthepregnancy(table3).Aprospective,randomizedstudyofcontinuousantimicrobialtherapytotheendofpreg-nancycomparedwith14daysofnitrofurantoinorsulfameth-izole,followedbyweeklyurineculturescreeningandre-treat-mentifbacteriuriarecurred,reportedsimilaroutcomesforthe2treatmentgroups[65].ArecentCochranesystematicreviewconcludedthattherewasinsufÞcientevidencetorecommendadurationofantimicrobialtherapyforpregnantwomenamongsingle-dose,3-day,4-day,and7-daytreatmentregimens[66].Thus,theoptimaldurationofantimicrobialtherapyfortreat-mentofbacteriuriainpregnantwomenhasnotbeendetermined.Theappropriatescreeningtestisaurineculture[67].Screen-ingforpyuriahasalowsensitivityÑonly50%foridentiÞ-cationofbacteriuriainpregnantwomen[25].TheoptimalfrequencyofscreeningisnotwelldeÞned.Womenwithaneg-ativeurinecultureresultforasinglescreeningspecimenat12Ð16weekshavea1%Ð2%riskofdevelopingpyelonephritislaterinpregnancy(table3).Whatproportionofthismaybepre-ventedwithrepeatedroutinescreeningisnotknown.Asingleurinesampleobtainedforcultureatweek16ofgestationwasconcludedtobeoptimalinaSwedishstudy[68].AnAmericancostevaluationfromtheviewpointoftheoutcomeofpyelo-nephritisconcludedthatasinglescreeningcultureintheÞrsttrimesterwascost-effectiveiftheprevalenceofbacteriuriawas2%andtheriskofpyelonephritisinbacteriuricwomenwas13%[69].Pregnantwomenshouldbescreenedforbacteriuriabyurinecultureatleastonceinearlypregnancy,andtheyshouldbetreatediftheresultsarepositive(A-I).Thedurationofantimicrobialtherapyshouldbe3Ð7daysPeriodicscreeningforrecurrentbacteriuriashouldbeun-dertakenaftertherapy(A-III).Norecommendationcanbemadefororagainstroutinerepeatedscreeningofculture-negativewomeninthelaterphaseofpregnancy.DiabeticWomenProspective,cohortstudiesofdiabeticwomenreportnodif-ferencesinratesofsymptomaticurinaryinfection,mortality,orprogressiontodiabeticcomplicationsbetweeninitiallybac-teriuricandnonbacteriuricwomenat18months[70]or14years[71]offollow-up.Arandomized,controlledtrialofan-tibiotictherapyornotherapyfordiabeticwomenwithasymp-tomaticbacteriuriaandcontinuedscreeningforbacteriuriaevery3monthsreported,afteramaximumof3yearsoffollow-up,thatantimicrobialtherapydidnotdelayordecreasethefrequencyofsymptomaticurinaryinfection,nordiditdecreasethenumberofhospitalizationsforurinaryinfectionorothercauses[72].Therewasnoaccelerationofprogressionofdiabeticcomplications,suchasnephropathy,inbacteriuricsubjectswhodidnotreceiveantimicrobialtherapy.Diabeticwomenwhoreceivedantimicrobialtherapy,however,had5timesasmanydaysofantimicrobialuseandsigniÞcantlymoreadversean-timicrobialeffects.Thus,therewerenobeneÞtsforcontinuedscreeningandtreatmentofasymptomaticbacteriuriaindiabeticwomen,andtherewasevidenceofsomeharm.Screeningforortreatmentofasymp-tomaticbacteriuriaindiabeticwomenisnotindicated(A-I). CID2005:40(1March)Nicolleetal.tomaticurinaryinfection[34,82].Whenasymptomaticbac-teriuriawasuniformlytreatedinacohortofcatheter-free,pri-marilymale,spinalcordÐinjuredsubjects,earlyrecurrenceofbacteriuriaaftertherapywastheusualoutcome.After7Ð14daysofantibiotictherapy,93%ofsubjectswereagainbacter-iuricby30daysaftercompletionoftherapy,andaftera28-daycourseofantibiotictherapy,85%werebacteriuricby30days[83].Reinfectingstrainsshowedincreasedantimicrobialresistance.When52patientswitharelativelyrecentonsetofspinalcordinjurywereobservedprospectivelyfor4Ð26weeks,theresultsof78%ofweeklyurinecultureswerepositive,butonly6symptomaticepisodesoccurred,allofwhichrespondedpromptlytoantimicrobialtreatment[84].Inasmall,random-ized,placebo-controlledtrial,ratesofsymptomaticurinaryin-fectionandrecurrenceofbacteriuriaweresimilaramongre-cipientsofeitherantimicrobialorplaceboforpatientswithbladderemptyingmanagedbyintermittentcatheterization[85].Aprospective,randomizedtrialofantimicrobialtreatmentornotreatmentofasymptomaticbacteriuriaenrolled50patientswhoweretreatedwithintermittentcatheterizationandreportedasimilarfrequencyofsymptomaticurinaryinfectionduringanaverageof50daysoffollow-up,irrespectiveofwhetherprophylacticantimicrobialsweregiven[86].Althoughtherehavebeenalimitednumberofclinicaltrials,andalthoughinterpretationofresultsiscompromisedbyrelativelyshortdu-rationsoffollow-upandsmallstudynumbers,reviewarticles[87,88]andconsensusguidelines[89]uniformlyrecommendtreatmentonlyofsymptomaticurinarytractinfectioninpa-tientswithspinalcordinjuries.AsymptomaticbacteriuriashouldnotbescreenedforortreatedinspinalcordÐinjuredpatients(A-II).PatientswithIndwellingUrethralCathetersShort-termcatheters.Approximately80%ofacutecarefa-cilitypatientswithshort-term(30days)indwellingurethralcathetersreceiveantimicrobialtherapy,usuallyforanindicationotherthanurinaryinfection[90,91].Thishighfrequencyofconcurrentantimicrobialusemakesassessmentofoutcomesuniquetotreatmentofasymptomaticbacteriuriaproblematic.Aprospective,cohortstudyof235catheter-acquiredinfectionsamong1497patients,90%ofwhomwereasymptomatic,re-portedonly1secondarybloodstreaminfection[92].Acase-controlstudyreportedthatacquisitionofbacteriuriawithin-dwellingurethralcatheterizationincreasedmortality3-fold,buttheexplanationforthisassociationwasnotclear,andmulti-variateanalysisfoundthatantimicrobialtherapydidnotaltertheassociationwithmortality[93].Aprospective,randomized,placebo-controlledtrialoftreatmentoffunguriain313pa-tients,morethanone-halfofwhomhadindwellingurethralcathetersinplace,showednodifferencesineradicationoffun-guria2weeksaftertherapyforcatheterizedsubjectsandnoclinicalbeneÞtsoftreatment[94].Aprospective,randomized,placebo-controlledtrialofan-timicrobialtreatmentofasymptomaticbacteriuriapersisting48hafterremovalofshort-termcathetersinwomenwithcatheter-acquiredbacteriuriareportedsigniÞcantlyimprovedmicrobi-ologicandclinicaloutcomesat14daysintreatedwomen[95].Although15(36%)of42womenrandomizedtoreceivenotherapyhadspontaneousmicrobiologicresolutionby14days,7(17%)developedsymptoms.Nowomeninthetreatmentgroupbecamesymptomatic.Thisstudyenrolledaselectedgroupofhospitalizedwomencharacterizedbybeingrelativelyyoung(medianage,50years)andexperiencingashortperiodofcatheterization(medianduration,3days).Long-termcatheters.Aprospective,randomizedtrialofcephalexintherapyversusnoantibiotictherapyforbacteriuricpatientswithlong-termindwellingurethralcathetersinplaceanddrug-susceptibleorganismsisolatedreportedasimilarin-cidenceoffeveramongbothtreatedanduntreatedpatientsobservedfor12Ð44weeks[96].Ratesofreinfectionwerealsosimilar,but75%ofreinfectingorganismsinthecontrolgroupremainedsusceptibletocephalexin,comparedwithonly36%inthecephalexintreatmentgroup.Aprospective,noncom-parativestudyofconsecutivecoursesofantimicrobialtreatmenttoeradicatebacteriuriainelderlypatientswithlong-termcath-etersreportednodecreaseinthenumberofepisodesoffeverwithtreatment,comparedwiththepretreatmentperiod,andtherewasimmediaterecurrenceofbacteriuriaaftertherapy,oftenwithorganismsofincreasingresistance[97].Asymptomaticbacteriuriaorfunguriashouldnotscreenedforortreatedinpatientswithanindwellingurethralcatheter(A-I).Antimicrobialtreatmentofasymptomaticwomenwithcath-eter-acquiredbacteriuriathatpersists48haftercatheterremovalmaybeconsidered.(B-I)UrologicInterventionsPatientswithasymptomaticbacteriuriawhoundergotraumaticgenitourinaryproceduresassociatedwithmucosalbleedinghaveahighrateofpostprocedurebacteremiaandsepsis.Bacteremiaoccursinupto60%ofbacteriuricpatientswhoundergotran-surethralprostaticresection,andthereisclinicalevidenceofsepsisin6%Ð10%ofthesepersons[98].Retrospectiveanalysis[99]andprospective,randomizedclinicaltrials[100Ð103]sup-porttheeffectivenessofantimicrobialtreatmentinpreventingthesecomplicationsinbacteriuricmenundergoingtransurethralresectionoftheprostate.Inonecomparativetrial,theefÞcacyofcefotaximewassuperiortothatofmethenaminemandelate[101].Thereislittleinformationrelevanttootherprocedures,butanyinterventionwithahighprobabilityofmucosalbleeding 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