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AmericanUrogynecologicSocietyBestPracticeStatement


RecurrentUrinaryTractInfectioninAdultWomenLindaBrubakerMDCassandraCarberryMDRahelNardosMDCharelleCarter-BrooksMDandJerryLLowderMD1KeyWordsUTIrecurrentUTIurinarytractinfectionsFemalePelvicMedReconstrSu

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Document on Subject : "AmericanUrogynecologicSocietyBestPracticeStatement"β€” Transcript:

1 AmericanUrogynecologicSocietyBest-Practi
AmericanUrogynecologicSocietyBest-PracticeStatement: RecurrentUrinaryTractInfectioninAdultWomen LindaBrubaker,MD,*CassandraCarberry,MD, † RahelNardos,MD, ‡ CharelleCarter-Brooks,MD,§andJerryL.Lowder,MD  KeyWords: UTI,recurrentUTI,urinarytractinfections ( FemalePelvicMedReconstrSurg 2018;00:00 – 00) F emalepelvicmedicineandreconstructivesurgery(FPMRS) specialistsprovidecareforwomenwithrecurrenturinarytract infection(rUTI).Inastudyofmorethan1100urogynecologic patients,investigatorsreportedapatient-reportedrUTIpreva- lenceof19%. 1 However,clinicalcarevaries becauseofalack ofevidenceandbestpractices.Inaddition,variablerUTIdefini- tionsexacerbatethegapinourunderstandingofthiscommon clinicalproblem.Inthecontextofevolvingevidenceandre- viewsonrUTI,thisdocumentsummarizescurrentbestpractice forrUTIdiagnosisandmanagementinwomen.Thesebest practicesdonotapplytowomenwhoarepregnant,areimmuno- suppressed,havesurgicallyalteredurinarytracts(notincluding typicalsurgeryforstressurinaryincontinenceorpelvicorgan prolapse),orregularlyuseurinarycathetersexceptwherespeci- fied.Inaddition,thisdocumentdoesnotcoverdiagnosisor treatmentofasymptomaticbacteriuria. TerminologyandDefinitions Acommonlyuseddefinitiondescribesurinarytractinfection (UTI)asaninfectionofthelowerand/oruppergenitourinarytract whichisdiagnosedbasedonthepresenceofapathogenintheuri- narytractandassociatedsymptoms. 2 Thisdefinitionassumesthat thesymptomsarecausedbythedetecteduropathogens.However, neithertheuropathogendetectionmethodnoranyspecific symptomsareinherentinthisUTIdefinition.Althoughthe umbrellatermUTIformallyincludesbothupperandloweruri- narytracts,thetermUTIisoftenusedinterchangeablywith cystitis(moreaccuratelybacterialcystitis).Thereislimitedevi- dencetosupportany “ goldstandard ” UTIdefinitionforepidemi- ologicorclinicalresearch. TherearemultipledefinitionsforrUTI.Thisbest-practice statementendorsesaclinicallyuseful,culture-baseddefinition: atleast2culture-provenepisodesin6months,oratleast3in 1year. 3 Itisassumedthattheseepisodesareseparateevents;how- ever,thereisnoconsensusastodiagnosticrequirementstodocu- mentresolutionofanyepisode,suchasaposttreatmentculture. DiagnosisandcareofrUTIpatientsdoesnotrequireuseofthe varioustermsproposedtofurthersubtypefrequentUTI,although thepresenceofpersistentorganismsmayalterthediagnostic and/ortreatmentapproach(eg,earliersearchforforeignbodyor urinarystone).Relapseindicatesthatthesameuropathogen causesUTIsymptomswithin2weeksofcompletingappropriate antibiotictherapy.Recurrencespecificallyappliestosituations inwhichthereisevidencethatthesubsequentUTIoccurredbe- yondtheinitial2weeksorwithadifferenturopathogen. 4 Epidemiology EstimatesofUTIincidencevarybasedontheresearchdefini- tionofUTIbeingusedandthelikelyoveruseofUTIcodesbefore acompleteddiagnosticevaluation.Commonlycitedreferencessug- gestthatmorethan8millionambulatoryvisits(84%women)inthe UnitedStatesin2007wereduetoUTI;21%wereemergencyde- partmentvisits. 5,6 Usingawoman'sreportofaphysiciandiagnosis ofUTI,theNationalHealthandNutritionExaminationSurvey datareporteda12.6%annualincidenceofUTIinwomen18years orolder. 7 Inamixed-sexpopulationofmorethan30,000patients whoseUTIdiagnosishadurinecultureconfirmation,Canadian investigatorsreportedtheannualUTIincidenceinwomenaged 20to79yearsas3%to5%andthoseaged80to89yearsas 12%.Twopercentofthesewomenhadatleast6UTIsin2years. 8 AfterasingleUTI,30%to44%ofwomenwillhaveare- currentUTI;50%willhaveathirdepisodeiftheyhavehad2 UTIsin6months. 3 InastudyofcollegewomenwithaUTI, 19%experiencedrecurrencewithin6months. 9 Inarecentstudy, Fromthe*DivisionofFemalePelvicMedicineandReconstructiveSurgery,De- partmentofReproductiveMedicine,UniversityofCaliforniaSanDiego, SanDiego,CA; † DivisionofUrogynecologyandReconstructivePelvicSur- gery,DepartmentofObstetricsandGynecology,AlpertMedicalSchoolof BrownUniversity,Providence,RI; ‡ DivisionofFemalePelvicMedicineand ReconstructiveSurgery,DepartmentofObstetricsandGynecology,Oregon Health&SciencesUniversity,Portland,OR;§DivisionofUrogynecologyand ReconstructiveSurgery,DepartmentofObstetrics,GynecologyandReproduc- tiveSciences,UniversityofPittsburgh,Pittsburgh,PA;and  DivisionofFemale PelvicMedicineandReconstructiveSurgery,DepartmentofObstetricsandGy- necology,WashingtonUniversityinStLouis,StLouis,MO. Reprints:LindaBrubaker,MD,UniversityofCaliforniaSanDiego,9500 GilmanDrive,MC0971,LaJolla,CA92093. E  mail:librubaker@ucsd.edu. Disclosures:Brubakerhasreceivededitorialstipends(FemalePelvicMedicine andReconstructiveSurgery,UptoDate).Theremainingauthorshaveno disclosurestoreport. ThisdocumentwasdevelopedbytheAmericanUrogynecologicSociety GuidelinesandStatementsCommitteewiththeassistanceofLinda Brubaker,CassandraCarberry,RahelNardos,CharelleCarter-Brooks,and JerryLowder.Thispeer-revieweddocumentreflectsclinicalandscientific advancesasofthedateissuedandissubjecttochange.Theinformation shouldnotbeconstruedasdictatinganexclusivecourseoftreatmentor proceduretobefollowed. AllWritingGroupmembersdisclosedcommercialandfinancialrelationships. WritingGroupmemberswhowerefoundtohaveconflictsofinterestbased ontherelationshipsdiscloseddidnotparticipateinthefinalapprovalofthis document. ExecutiveSummary „ BestpracticesinthecareofwomenwithrUTI: MaketherUTIDiagnosis: UTI,culture-docume

2 ntedepisodes(  2in6monthsor  3in
ntedepisodes(  2in6monthsor  3in12months). UrineTesting: Avoiddipstickassoletest UseUAifknowledgeofpyuriaaltersyourcare Avoidreflexurineculture Interpretpretreatmenturinecultureandsensitivitieswithknowledgeoflocal resistancepatterns;considerposttreatmenturineculture CodeCorrectly:SeeTable1. TreatOptimally:Usenitrofurantoin,TMP-SMXorfosfomycinasfirst-line agentswheneverpossible. ReduceRecurrenceRisk:Basedonspecificclinicalfactorsforaffectedwoman. Nonantibioticstrategies: Vaginalestrogeninhypoestrogenicwomenwithoutcontraindication. Considermethenamine. Prophylacticantibioticregimens(ensurenegativeurineculturebeforeinitiating prophylaxis): Postcoitallow-doseantibiotic,ifcoitallyassociatedepisodes. Judicioususeofdaily,low-doseoralantibiotic. Copyright©2018WoltersKluwerHealth,Inc.Allrightsreserved. DOI:10.1097/SPV.0000000000000550 AUGSG UIDELINES FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018www.fpmrs.net 1 Suskindetal, 10 usingadatabaseofhealthcareclaims,studied womenaged18to64yearswhohadanevaluationandmanage- mentvisitassociatedwithan InternationalClassificationofDis- ease,NinthRevision codeforUTIandanantibioticprescription within14daysofthatvisit.Theyreportedanoverallrateofinci- dentrUTIcasesof102per100,000womenperyear,withthe highestratesinwomen18to34yearsoldand55to66yearsold. Pathophysiology Adjacentpelvicmicrobialnichesserveasreservoirsfor uropathogensthatcanleadtoUTI/rUTI. 11 Currently,themajority ofevidenceforuropathogensintheurinecomesfromstandard urineculturetechniques,whichhavebeenrefinedtodetect Escherichiacoli .Standardculturesalsodetectothercommon pathogensincluding Klebsiella species, Staphylococcussaprophyticus , Enterococcusfaecalis ,and Streptococcusagalactiae. Culture- independenttechniques,suchaspolymerasechainreactiontesting andsequencing,confirmthatstandardurineculturesdonotde- tectalluropathogensorotherresidentmicrobesoftheurinary microbiota. 11 Enhancedculturetechniquescomplementculture- independentmethodstoadvanceourunderstandingofUTIand rUTIprevention,pathogenesis,treatment,andrecoverybutare notyetwidelyavailableforclinicaluse. Currentevidence,basedonstandardcultures,indicates that E.coli causesmost(70% – 95%)community-acquired UTIs.Studiesinolderwomensuggestthat E.coli accounts formorethanhalfofUTIs,whereasothercommonorganisms are Klebsiellapneumoniae , Proteusmirabilis ,and E.faecalis . E.coli isalsothemostcommoncauseofrUTI(66%).The uropathogensassociatedwithrUTIarethesamemicrobesassoci- atedwithepisodic(non-rUTI)UTIepisodes.However,non – E. coli pathogensandresistantorganismsaremorelikelytobeasso- ciatedwithUTIepisodesinwomenwithrUTI. 3,7,12 E.coli hasmultiplestrainsandvirulencefactors. 13 Uro- pathogenic E.coli (UPEC)hasbeenwidelystudiedinmurine models,andsomefindingshavebeenverifiedinhumanstud- ies. 14,15 Uropathogenic E.coli havespecialfeaturesthatfacilitate urothelialattachment,allowingthemicrobetotakeupresidence withinthebladder. 14,15 Uropathogenic E.coli canformintracellu- larbacterialcommunitiesthatactlikeabiofilm,allowingbacteria topersistinquiescentintracellularreservoirs,actingasasourceof recurrentinfection. 16,17 EpisodesofrUTIsareoftenassociated withthesamebacterialstrain;thishasimportantimplications fortreatment,highlightingtheneedforcarefulantimicrobialsen- sitivitytestingandtreatmentselection. Inadditiontobacterialfactors,hostfactors,includinghor- monalstatus,anatomy,functional,andbehavioralvariables,and geneticfactorslikelymodulateUTIandrUTIsusceptibility. 3,14,18 Forexample, E.coli hasanincreasedabilitytoadheretothe urotheliuminwomenwhoarenonsecretorsofcertainblood groupantigens. 3,19 Individualfactors,suchaspre-UTImicrobiota/ microbiomehealth,degreeofinflammation,andurothelialexfo- liationfromaninfection,mayaffectresponsetoUTI,recovery fromUTI,andsusceptibilitytofutureUTI. 13,14 RiskFactors Manycommonlyrecommendedbehaviorshavenotbeenes- tablishedasreducingriskforrUTI(wipingawayfromtheurethra; voidingbeforeandafterintercourse;increasingfrequencyof voiding;wearingcertaintypesofunderwear;avoidingdouching; oravoidinghottubs,bubblebath,ortampons). 3 Physiciansshould considerthecontributionofgrossfecalsoilage,asinwomenwith fecalincontinence. ApersonalhistoryofUTIbeforeage15yearsandmaternal UTIhistoryarerUTIriskfactors. 3,20 Acase-controlstudyofmore than400womenreportedanincreasedriskofrUTIsinwomen havingafirst-degreefemalerelativeswithahistoryofatleast 5UTIs. 21 Sexualriskfactors,suchasanewsexualpartner,in- tercoursefrequency,andspermicideuse,aremorecommonin premenopausalwomen. 21 Womenwithpelvicfloordisordersareatincreasedriskfor rUTIs,especiallypostmenopausalwomenwithurinaryinconti- nence.Someinvestigatorssuggestanassociationbetweenpost- voidresidualofatleasy50mLandrUTI. 19 Theassociation withprolapseisunclear. 22 ThereisariskofrUTIaftersurgeryforstressurinaryincon- tinence.Theearlypostoperativeperiodisassociatedwithatran- sientincreasedrUTIrisk(11%)afterretropubictension-free vaginaltapewithorwithoutconcomitantprolapserepair. 23 Be- yondthefirst6postoperativeweeks,investigatorsreportedrUTI in2.3%to2.4%ofparticipantsin2randomizedsurgicaltrials (StressIncontinenceSurgicalTreatmentEfficacytrialandTrial ofMid-UrethralSlings). 24 Between2and12months,women whohadamidurethralslinghadapostoperativerUTIrateof

3 2.3%. 25 NocasesofrUTIwerereporteddurin
2.3%. 25 NocasesofrUTIwerereportedduringarecent10-year follow-upof71womenwhohadtransobturatormidurethralslings. 26 DIAGNOSIS WomenwithfrequentUTImayexperiencediagnosticdelay ifcliniciansdonotreviewtheUTIhistory;cliniciansshouldorder pretreatmenturineculturestodocumentrUTI(culture-provenUTI  2in6monthsor  3in12months). 3 AlthoughinfrequentUTI canbeassessedwithlessrigorandtreatedempirically,women withfrequentUTIwhoarebeingformallyassessedforrUTI shouldhavedetailedsymptomassessmentandpretreatmenturine cultureandsensitivity. 4 Symptoms Dysuriaisakeysymptomofbacterialcystitis.Frequency, urgency,hematuria,andsuprapubicpainarevariablypresent. Symptomsofflankpain,feverandchills,andnauseaandvomit- ingshouldpromptconsiderationofpyelonephritis.Inyoungwomen, thereisa90%probabilityofaUTIwhenshereportsdysuriaand frequencyintheabsenceofvaginaldischargeorirritation. 6 The accuracyofhistoryandphysicalexaminationforUTIdiagnosis inwomensuggestsanincreasedUTIprobabilitywithdysuria (likelihoodratio[LR],1.5;95%confidenceinterval[CI],1.2 – 2), frequency(LR,1.8;95%CI,1.3 – 3),hematuria(LR,2.0;95%CI, 1.3 – 2.9),backpain(LR,1.6;95%CI,1.2 – 2.1),andcostovertebral angletenderness(LR,1.7;95%CI,1.1 – 2.5).Theprobabilityof UTIdiagnosisisreducedwithahistoryofvaginaldischarge (LR,0.3;95%CI,0.1 – 0.9)orvaginalirritation(LR,0.2;95% CI,0.1 – 0.9). 27 Withaging,symptomspotentiallyassociatedwithaUTI maybelessclear.Acutedysuriaremainsareliablesymptom, new-onsetfrequencyorurgencyhasbeenfoundtocorrelate withUTI,andnew-onseturinaryincontinenceshouldprompt evaluationforUTI. 28,29 Nontraditionalsymptoms,suchasurinary odororurinaryappearance,maybetriggersforurogynecologic patientstoseekcareforpresumedUTI. 2,3,30 Womenwithcogni- tivelimitationsmayhavedifficultyreportingsymptoms;family/ caregiversmayalerthealthcareproviderstochangesinmentation orenergylevels,whichmayindicateUTI,althoughthisisadiag- nosticchallenge. 2 Despitethecommonclinicalobservation,wors- eningofchronicincontinenceorotherurinarysymptomsarenot reliablyassociatedwithUTI. 2,31 Brubakeretal FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 2 www.fpmrs.net ©2018WoltersKluwerHealth,Inc.Allrightsreserved. ThereissignificantsymptomoverlapbetweenUTIandmany urogynecologicconditions,incl udingurgencyurinar yincontinence, overactivebladder,andbladderpainsyndrome.Currently,ourun- derstandingofappropriatesymptomattributioninthispatient populationislacking. UrineDipstick Theurinedipstickhasvaluetoruleout,ratherthanrulein, UTIinpatientswithlowerpretestprobablyofUTI.Because womenwithrUTIdonothavealowpretestprobabilityofUTI, dipsticktestingisnotadvisedandpretreatmenturineculture isnecessary. Urinalysis Beyondthestandardindicationsfortesting(hematuria,pro- teinuria,etc),urinalysisinwomenwithrUTIcanconfirmpyuria (atleast10whitebloodcellsperhigh-powerfield).Theinterpre- tationofpyuriaforwomenwithrUTIremainsdebatablebecause ofalackofrelevantstudiesinurogynecologicpopulations.When thefindingofpyuriawouldalterthetreatmentplan,theclinician shouldobtainaurinalysis. UrineCulture ThecriteriaforUTIdiagnosisbyurineculturevariesand hasnotbeenvalidatedinanyurogynecologicpopulation.The standardurineculturealongwithmicroscopicurinalysishasbeen usedasacriterionstandardforconfirmingsuspectedUTI.Apos- itivecultureistypicallycharacterizedbybacteriuriaofatleast 10 5 colony-formingunits(CFU)/mL, 32 althoughaccordingto theEuropeanAssociationofUrologyguidelines,acountof 10 3 CFU/mLinsymptomaticpatientsissufficientfordiagnosis. 33 TheSocietyofObstetriciansandGynaecologistsofCanadaclini- calpracticeguidelinesstatethateven10 2 CFUissufficientin thesettingofUTIsymptoms. 32 Cliniciansshouldhaveaclearun- derstandingoftheirclinicallaboratoryprotocolsascertainlabora- toriesmayreport10 4 orlessas “ nogrowth. ” Bestpracticesforposttreatmenttestofcure(test-treatment- test)urineculturevaryandarebasedonexpertopinion.Reliance onsymptomaticresolutionaloneforgoestheabilitytodetectpat- ternsofuropathogenpersistenceorrecurrence. 20 TheCanadian UrologicalAssociationguidelinessuggestrepeatingaurinecul- ture1to2weeksaftertreatmenttotestforpersistence. 4 Arepeat urineculturemayallowfordetectionofpatternsofuropathogen persistenceorrecurrencethatmayprovideinsightintotheetiol- ogyoroptimaltreatment. 20 Anegativeposttreatmenturineculture providesevidenceofeffectivetreatment.Intheabsenceofaneg- ativeposttreatmenturineculture,itispossiblethat2or3UTIep- isodesarerelatedtoasinglepersistenturopathogen. However,cliniciansfaceadilemmawhentheposttreatment cultureispositiveandthepatient'sUTIsymptomshaveresolved. Someexpertswhobelievethatwomenwithanactivediagnosis ofrUTIcanalsocarryadiagnosisofasymptomaticbacteriuria recommendagainstposttreatmenttestingtoreducetheriskof treatingasymptomaticbacteriuriaandlessenantibioticexposure. 2,3,34 Youngwomenwithasymptomaticbacteriuriaparticipatingin arandomizedtrialwhoweretreatedwere(1)morelikelytode- velopsubsequentinfectionsatahigherratethanthosewho werenottreatedand(2)morelikelytodevelopantibiotic- resistantorganisms. 34,35 PhysicalExamination Althoughaphysicalexaminationmaynotbenecessarybe- foretreatmentforawomanwithinfrequentUTI,anexamination shouldalwaysoccuraspartoftherUTIevaluationtodetectanun- derlyingetiology,potentialcontributors(hypoestrogenism

4 ),and findingssuggestiveofuppertractinvo
),and findingssuggestiveofuppertractinvolvement.Inadditiontoan assessmentofthepatient'sgeneralstatus,focusedexamination shouldincludepalpationforcostovertebralangleandsuprapu- bictenderness.Thepelvicexamination,includingbimanual,can checkforvulvarskinand/orarchitecturechanges,urethraldiver- ticulum,tendernessinpelvicfloormuscles,urethraorbladder, vaginaldischarge,andpelvicmasses.Inaddition,detectionofpel- vicorganprolapse,presenceofaforeignbodysuchasaretained pessary,orerodedmeshorsutureswillinformthetreatmentplan. Theseassessmentsshouldbeperformedwithinitialevaluationof apatientwithrUTIandrepeatedasneededdependingonstatus changes,includingnewsigns,symptoms,orriskfactors. AdditionalTesting PostvoidResidual Apostvoidresidualshouldbemeasuredtoensurethatthere isnosignificanturinaryretention.Thiscanbedoneatthetimeof thephysicalexamination. ImagingandEndoscopy Therearecurrentlynospecificguidelinesforimagingstud- iesforwomenwithrUTI.Indicationsforimaginginwomenwith UTIincludepersistentsymptoms(persistentfeverafter72hours ofappropriateantibiotictherapy),rapidrecurrenceafterappro- priatetreatment,suspectedstoneorobstruction,andwomenwith diabeteswhoareathigherriskforcomplicationssuchasabscess, emphysematouspyelonephritis,andsoon. 35,36 Cystourethros- copyshouldbeconsideredifawomanisatriskforsuspected foreignbodywithinthebladderorurethra,althoughtheutility ofcystoscopyinevaluationofrUTIhasnotbeenwellstudied. Oneretrospectivestudyreportedthat3.8%ofthe163participants hadspecificfindingsoncystoscopythatimagingwouldnotde- tect. 37 Cystoscopywithcytologyshouldbeperformedwhenthere isclinicalsuspicionforpremalignancyormalignancy.Assess- mentforurinarytractstonescanbeinitiatedwithplainabdominal radiographs.Whentheclinicalsituationwarrantsmorecom- pleteassessmentoftheuppertracts,renalultrasound,orcom- putedtomographicurographyshouldbeused.Ingeneral,a computedtomographicurogram,whichiswithandwithoutintra- venouscontrast,istheimagingmodalityofchoiceinpatients suspectedofhavingpyelonephritis,andrenalandperirenalab- scess.Thismodalitycanalsoidentifyapossiblesourceofinfec- tionsuchasrenaloruretericstones. 38 CodingandDocumentation WomenwhomeetthecriteriaforrUTIshouldhavethisdiag- nosisaddedtotheirproblemlisttohelpalertotherproviderstothe recurrentnatureoftheUTIsandtohelpensurethatbestpractices arefollowedforevaluationandtreatment.Inaddition,methodsto trackUTIs(date,pathogen,antibioticprescribed)canbedevel- opedinsummaryorflowsheetsinthemedicalrecord. Accurateuseof InternationalClassificationofDisease,10th Revision,ClinicalModification ( ICD-10-CM )isimportantfor correctclassificationofpatientsforclinicaldiagnosisandpopula- tionstudiesofrUTI.Table1describesmanyofthe ICD-10 codes associatedwithlowerUTI.The ICD-10 codeof “ positiveurine culture ” canbeusedinsteadofUTIorasymptomaticbacteriuria whenaurinecultureispositivebuttheclinicalcriteriaarenot metforaUTI:forexample,ifapatientisasymptomaticandacul- tureisinadvertentlyobtainedbeforetreatmentcompletionor FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 RecurrentUTIinAdultWomen ©2018WoltersKluwerHealth,Inc.Allrightsreserved. www.fpmrs.net 3 whilethepatientisonsuppressionbutasymptomatic.Wepropose providersreplacetheactiverUTIdiagnosiswithhistoryofrUTI after1yearoftheaffectedwomannolongerbeingtreatedfor rUTIandnotmeetingthecriteriaforthediagnosisofrUTI. TREATMENT TreatmentoptionsforrUTIscanbestratifiedbywhether complicatingfeatures,suchasabnormalgenitourinaryanatomy, immunosuppression,andchroniccatheterization,arepresent. Moststudieshavefocusedonoralorparenteralantibiotictherapy, whereasdataonintravesicalandnonantibiotictreatmentsarelimited. Antibiotictherapyistypicallyusedtotreatactiveinfections andpreventfutureinfections;thetreatmentregimen,route,and durationwillvarybasedontheclinicalsituationandshould beindividualizedfor eachpatient.Variousantibiotictreatment strategieshavebeendescribedforsymptomaticpatientswith recurrentinfections.Thesecanbedividedintotreatmentof anacuteepisode(providerprescribedorself-treatment)orpro- phylaxis(topreventfurtherepisodes).Wheneverpossible,rUTI patientsshouldhaveaculturesentbeforetreatment.Empiric therapycanbeinitiatedbeforeurinecultureresultsifclinicallyin- dicated(suchashistoryofUTI-relatedsepsisorpyelonephritis). Antibioticchoiceshouldbetailoredtotheindividualpatientand pathogens,communityandpatientresistancepatterns,costs,drug availability,patientallergies,andpatienttolerance/abilitytocom- ply. 39 Providersshouldbefamiliarwiththeantibiotic-resistant patternsintheircommunitieswhichisgenerallyavailablevia antibiogramsthroughanyclinicallaboratory.Empiricregimens shouldbealteredifnecessarybasedontheurinecultureresults. TreatmentofUTIinWomenWithRecurrentUTI WithoutComplicatingFeatures TreatmentrecommendationsforacuteUTIinwomenwith rUTIhavebeenextrapolatedfromacuteUTItreatmentinwomen withoutrUTI.Conditionaltreatmentandantibiotictherapyarethe 2treatmentapproacheswithevidenceofefficacyinuncompli- cated,bacterialcystitis. 40 – 44 TABLE1. ICD-10-CM UTITerminology ICD-10-CM TerminologyCodeClinicalScenarioforSuggestedUse Activeinfection € Bladderinfection,acute € Acutecystitiswithouthematuria € Acuteonchroniccystitis N30.00Acute/activeinfectionofthebladderwithouthematuria € AcutecystitiswithhematuriaN

5 30.01Acute/activeinfectionofthebladderwi
30.01Acute/activeinfectionofthebladderwithhematuria € Bladderinfection,chronic € Chroniccystitis N30.20Chronicinfectionofthebladder € ChroniccystitiswithhematuriaN30.21Chronicinfectionofthebladderwithhematuria € Cystitis,unspecifiedwithouthematuria € Bacterialcystitis € Recurrentbacterialcystitis N30.90Recurrentbacterialinfectionofthebladder € UTIN39.0Acute/activeinfectionoftheurinarytract, sitenotspecified(shouldnotbeusedifsiteknown) € FrequentUTIN39.0Frequentinfectionoftheurinarytract,sitenotspecified; clinicianshouldbecomealertforpossiblerecurrent UTIdiagnosis € RecurrentUTIN39.0Recurrentinfectionoftheurinarytract,sitenotspecified (shouldnotbeusedifsiteknown) Historyofinfection € Historyofcystitis € Historyofacutecystitis Z87.440Historyofinfectionofthebladder € HistoryofrecurrentcystitisZ87.440Historyofrecurrentinfectionsofthebladder € HistoryofUTIZ87.440Historyofinfectionoftheurinarytract,sitenotspecified € HistoryoffrequentUTIZ87.440Historyoffrequentinfectionsoftheurinarytract,sitenotspecified € HistoryofrecurrentUTIZ87.440Historyofrecurrentinfectionsoftheurinarytract,sitenotspecified Other € AsymptomaticbacteriuriaR82.71+Urineculture,noUTIsymptoms,patientnotcurrently takingUTIantibiotics € PositiveurinecultureR82.79+Urineculturewithoutinformationregardingpatient symptomstatus Additionalcodestospecifyinfectiousagent(activeinfection) Enterococcus B95.2 K.pneumoniae B96.1 E.coli B96.2 Proteus B96.4 Pseudomonas B96.5 Ndenotes “ GenitourinarySystem, ” Z, “ FactorsInfluencingHealthStatusandContactwithHealthServices(similarto “ V-codes ” inpastcodingtermi- nology);R, “ Symptoms,SignsandAbnormalClinicalandLabFindings. ” Brubakeretal FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 4 www.fpmrs.net ©2018WoltersKluwerHealth,Inc.Allrightsreserved. Withconditionaltreatment,eitheranonsteroidalanti- inflammatorydrugisusedforsymptomaticrelieforpatientsare followedupwithoutanyformoftreatment.Antibiotictherapyis onlyinitiatedifsymptomsprogressordonotresolveinaclinically reasonabletimeframe.Conditionaltreatmenthasnotbeenstudied inwomenolderthan65yearsorwithrUTI.Severaltrialsin womenyoungerthan65yearshaveshowedresolutionratesof 20%to47%withoutantibiotictreatment. 40,41,45 However,one studydocumentedahigherrateofpyelonephritisintheplacebo groupat2%to2.6%. 45 Antibioticsaretraditionalfirst-linetreatmentofbacterial cystitisinwomenwithrUTI. 3 InwomenwithrUTI,acutetreat- mentcanbeinitiatedbyaclinicianorpatient(self-treatmentreg- imen)atthetimeofsymptomonset. 6 MoststudiesofacuteUTI treatmentwerenotperformedinwomenwithrUTIorotherpelvic floordisorders. PatientConsiderationsforSelectionof AntimicrobialAgent Allergies BeforeprescribingantibioticsforaUTI,theclinicianshould reviewdrugallergiesandintolerances.Patientsmayhavereported adversedrugreactions,sideeffects,and/orallergiestorecom- mendedfirst-lineUTIantibiotics.Suchpatientscanbefurther evaluatedtodeterminewhethertheyhavedrugsideeffect/adverse reactionvsatrueallergicreaction(Table2).Cliniciansshouldnot readministeranantibioticinpatientswithpreviouslyseverereac- tionssuchasStevens-Johnsonsyndromeunlessessentialforsur- vivalofthepatient. 48 Allergydesensitizationmaybeconsidered forpatientswithchallengingmicrobialresistancepatterns. RenalFunction Normalagingisassociatedwithadeclineintheestimated glomerularfiltrationrateandcreatinineclearance(CrCl);thisim- pactstheefficacyandtoxicityofmedicationsthatarerenally cleared,suchasnitrofurantoin(recommendedasfirst-lineUTI therapy).Patientswithdecreasedglomerularfiltrationrateare morelikelytoexperiencetreatmentfailureduetoreducedrenal elimination. 49 Nitrofurantoinisineffectivebecauseofinadequate urineconcentrationsinpatientswithaCrCloflessthan30mL/min. Prescribersshouldbefamiliarwithantibioticrouteofclearance andspecificrecommendationsforrenaldosingifindicated.Al- thoughmorethan25%ofindividualsatleast65yearsoldhavean estimatedglomerularfiltrationrateoflessthan60mL/min, changesinmicrobialagentordosebasedonagealoneare notrecommended. 49,50 Nitrofurantoinhasbeenunderusedbasedondecreasedrenal clearance,althoughupdatedguidelinessupportitsuseinprevi- ouslyrestrictedpopulations(CrCl60mL/minbut&#x-4.4;30mL/min). 49 TheAmericanGeriatricsSociety2015BeersCriteriaUpdateEx- pertPanelhasupdateditsrecommendationtodecreasetheCrCl thresholdforusingnitrofurantoinfrom60to30mL/minbased on2retrospectivestudies. 51 First-lineAntimicrobialAgents Fewstudiesexploretheoptimalantibioticchoiceinolder womenandwomenwithrUTI.IntheInfectiousDiseaseSociety ofAmericaguidelinesforpremenopausalwomen,3first-line antibioticsforUTItreatmentarerecommended:nitrofurantoin, trimethoprim-sulfamethoxazole(TMP-SMX)andfosfomycin 39 (Table3).Recommendationsareextrapolatedfromthese guidelinesforuseinrUTI,olderwomen,andwomenwith urogynecologicdisorders. Nitrofurantoinisbacteriostaticandtherapeuticallyactive onlyinthelowerurinarytract.Itiseffectiveagainst E.coli and manygram-negativespecieswithlowlevelsofresistance. 20,67 However,itisineffectiveagainstotheruropathogensincluding some Proteus speciesandsomestrainsof Enterobacter and Klebsiella. 20 Thedurationoftreatmentistypically7to10days. Arecentmeta-analysisofstudiesofwomenrangingfrom12to 70yearsoldwithvariableeligibilitycriteriaconcludedthat 5-dayregimensareaseffective, 67 alt

6 houghthismeta-analysis isnotnecessarilyg
houghthismeta-analysis isnotnecessarilygeneralizabletowomenwithrUTI.The 2010 “ Internationalclinicalpracticeguidelinesforthetreatment ofacuteuncomplicatedcystitisinwomen ” recommendsa5-day regimenof100mgorallytwicedaily. 39 Trimethoprim-sulfamethoxazoleisabroad-spectrumantibi- oticthatcoversgram-positivebacteriaincludingmethicillin- resistant Staphylococcusaureus andmostgram-negativebacteria, TABLE2. EvaluatingAdverseEventsvsAllergies 46,47 DefinitionsExamples SideeffectUndesirablepharmacologicaleffectatrecommendeddosesDrymouth,drowsiness AdversedrugreactionAnynoxiousorunintendedreactiontoa drugadministeredinappropriatedosesbytheproperroute Common:nausea,diarrhea,urticarial,rash, neurotoxicity,superinfection Infrequent:fever,vomiting,erythema,dermatitis, angioedema,seizures,pseudomembranouscolitis AllergyImmunologicallymediated,demonstratesimmunologic specificityandrecurrenceonreexposure TypeI:immediatehypersensitivity,IgEmediatedAnaphylaxis TypeII:cytotoxicreactions,IgGandIgMmediatedDrug-inducedhemolyticanemia TypeIII:immunecomplexreactions,IgGandIGMmediatedPost – streptococcalglomerulonephritis TypeIV:Tcell – mediatedreactionsContactdermatitis € Educatepatientsonthedifferencebetweenasideeffect,adversedrugreaction,andanallergicreaction.  Patientsmayhavebeentoldtheyhadanallergicreactionasachild,butinsomecases,theymayhavehadaviralskinrashoccurringcoincidentwith antibiotictreatment. € Patientsreportingahistoryconsistentwithanallergicreaction(eg,anaphylaxis,urticaria,angioedema,andbronchospasm)toanantibioticcan bere- ferredtoanallergistfordrugallergytesting(skinpricktest,radioimmunoassays,testdosechallenge)tohelpdocumenttrueallergicreactions.  RecurrenceriskoftypeIhypersensitivityreactionstoadrugaresubstantialandthosereactionsareoftenmoreseverethantheinitialreaction. FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 RecurrentUTIinAdultWomen ©2018WoltersKluwerHealth,Inc.Allrightsreserved. www.fpmrs.net 5 excluding Pseudomonas. Whenthereisgreaterthan20%local E.coli resistancetoTMP-SMX,analternativetreatmentshould begiven.ReporteddurationofTMP-SMXtreatmenthasranged from3to14days,withthe3-daycoursebeingfoundtohavesimilar efficacyto5-to10-dayregimens(seedurationoftherapy hereinafter). 39 Fosfomycintromethamine,thestablesaltformoffosfomycin, istakeninasingledosewhichishighlyconcentratedintheurine resultinginurinelevelsthatpersistfor30to40hours.Fosfomycin hasactivityagainstbothgram-positiveandgram-negativebacteria, including S.aureus , Enterococcus , Pseudomonasaeruginosa , and K.pneumoniae. 68 – 70 Fosfomycinhasmaintainedrelatively lowlevelsofresistance,makingitadrugofchoiceininfections withmultidrug-resistantorganisms. 2,69,71 – 73 Inaddition,fosfomycin isanimportanttherapeuticagentfortreatmentofextended- spectrumbeta-lactamase(ESBL) E.coli UTI. Second-lineAntimicrobialAgents Whenfirst-linemedicationsarenotavailableorcannotbe prescribedbecauseofpatientallergiesorintolerancesorbacterial resistance,second-lineantimicrobials,  -lactams,andfluoroquinolones canbeused.  -Lactams(suchascefiximeandcefpodoxime)havein vitroactivityagainstmostgram-negativeuropathogensexcept Pseudomonas .Randomizedtrialevidencesuggeststhattheeffec- tivenessof3-daycefpodoximeorTMP-SMXiscomparableat 98.4%vs100%. 52 Generally,cephalosporinshavealowercure ratethandidTMP-SMXandfluoroquinolones. 20 Lesswell-studied  -lactams,likecephalexin,canalsobeusediffirst-lineantibiotics areinappropriateforanyreason. 39 Although3-dayfluoroquinolonesre gimens(eg,ciprofloxacin andlevofloxacin)arehighlyefficacious,theyarenotfirst-line agentsbecauseofincreasingresistance,higherexpense,andseri- ousadverseeventsasdescribedina2016FoodandDrug Administrationwarning. 20,39,53,74 NotRecommended Unlessthereisclearevidenceofsensitivitytocertain  -lactams,includingamoxicillinandampicillin,theseantibiotics shouldrarelybeusedbecauseofpoorefficacythoughttobedue inparttothelackofconcentrationintheurine. 32,39 DurationofShort-courseTherapy Therecommendationforthedurationofacutebacterialcys- titistreatmentinwomenwithrUTIisnotevidencebasedandis extrapolatedfromwomenwithoutrUTI;someexpertsuselonger durationtherapyinrUTIwomen.Althoughitdidnotspecifically addresswomenwithrUTI,inaCohranesystematicreviewand meta-analysisof15randomizedcontrolledtrialsof1644elderly womencomparingantibioticdurationfortreatmentofacuteUTI, theauthorsfoundthatthestandarddurationforshort-coursetherapy (3 – 6days),comparedwith7to14days,wassufficienttreatment. 75 Thereviewalsoreportedthatsingle-dosetherapywasassociated withahigherrateofpersistentUT Icomparedwithshort-course therapy(riskratio[RR],2.01;95%CI,1.05 – 3.84).Ofthe15studies includedinthisreview,only2studiedfosfomycin. TABLE3. AntibioticRecommendationsforAcuteUTITreatmentinWomenWithrUTI 39,52 – 66 AntibioticRegimensforAcuteCystitisTreatmentEstimatedClinicalEfficacy First-lineantibiotics Nitrofurantoinmonohydrate/ macrocrystals 100mgBID  5d € Avoidifearlypyelonephritissuspected € Minimalresistance € Minimalriskofcollateraldamage 93%(84 – 95) Trimethoprim/sulfamethoxazole160/800mgBID  3d € Efficacyshowninnumerousclinicaltrials € Avoidifresistanceprevalenceknown tobe�20% 93%(90 – 100) Fosfomycintrometamol3gsingledose € Minimalresistance € Minimalriskofcollatera

7 ldamage € Avoidifearlypyelonephritissusp
ldamage € Avoidifearlypyelonephritissuspected € Lowerefficacythanotheragents € InvitroactivityagainstVRE,MRSA,and ESBLgram-negativerodssupportedwith clinicalstudies 91% Second-lineantibiotics FluoroquinolonesDosevariesbyregimen; typically3-dregimen € Resistanceprevalencehighinsomeareas € Highriskforcollateraldamage 90%(85 – 98)  -LactamsDosevariesbyregimen; typicallyfor3 – 7d € Donotuseampicillinoramoxicillinfor empiricaltreatment € Lowerefficacythanotheravailableagents duetohighresistanceanddecreased concentrationinthebladder € Requiresclosefollow-up 89%(74 – 98) Self-initiatedregimens Nitrofurantoinmonohydrate/ macrocrystals 100mgBID  5dSeeabove Trimethoprim/sulfamethoxazole160mg/800mg BID  3d Seeabove Fosfomycintrometamol3gSeeabove BID,twiceaday;MRSA,methicillin-resistant S.aureus ;VRE,vancomycin-resistantenterococci. Brubakeretal FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 6 www.fpmrs.net ©2018WoltersKluwerHealth,Inc.Allrightsreserved. Thisdocumentsupportsthepracticeofusingstandarddura- tiontherapyandtailoringtreatmentasclinicallynecessary.Theef- ficacyof3-dayregimensofTMP-SMXandfluoroquinoloneshas comparableeffectiveness(79% – 100%and85% – 98%curerates) andiswidelyacceptedforUTItreatmentintheabsenceofcom- plicatingfactors. 52 – 57,76.77 Theseregimensareaseffectivefor symptomaticreliefaslonger(5-to10-day)regimensandhaveim- provedcompliance,decreasedcosts,andlowerratesofadverse reactions. 20,39,78 Theefficacyof5daysofnitrofurantoiniscompa- rableto3daysofTMP-SMX. 53,67,79 Fivedaysofnitrofurantoin hasbetterefficacythana3-dayregimen. 40,67,80,81 Table4displays drug-relatedadverseevents. Self-treatmentWithAntibiotics(Patient-initiated Therapy/Self-startTherapy) Self-treatmentcanbeassociatedwithstandingphysician ordersforurineculturebeforeand,possibly,aftertreatment, tohelpmaintaindiagnosticclarity.Forwomenwhoaretraveling orotherwiseunabletosubmitaurinespecimen,rareepisodesof self-treatmentwithoutculturearepermissible.Comparedwith continuousprophylaxis,self-treatmentisassociatedwithahigher rateofinfection(2.2UTIperyearvs0.2UTIperyear). 87 Self- treatmentisanoptionforwomen(1)withtheabilitytoreliably recognizeUTIsymptomsandstartantibiotics,(2)whoarenot suitableforlong-termprophylaxis,or(3)whodonotwishtotake long-termtherapy. 4,87 – 90 Forself-treatment,cliniciansprescribetheappropriatedose anddurationofanantibioticthatwillcoverthemostlikely uropathogenbasedonthepatient'shistorysothatshecaninitiate treatmentbasedonhersymptoms.Womenwhousetheself- treatmentregimenshouldbecapableofcontactingtheirclinician ifsymptomsprogressorfailtoresolvewithin48hours.Table3 displaystherecommendedself-treatmentregimens.Antibiotic agentswithminimalsideeffectsarerecommendedtoimprovepatient complianceandminimizeadverseeventsandovertreatment. 91,92 Fluorquinolonesarenotpreferredagentsforself-treatment regimensdespitehistoricalsuccess,becauseofhighcost,riskof resistance,andadverseeventprofile.Werecommenduseofother agentswheneverpossible. 90 RecurrentUTIWithComplicatingFactors WomenwithrUTIwhohavecomplicatingfactors,suchas abnormalgenitourinaryanatomy,immunosuppression,andchronic catheterization,requireadditionalvigilanceindiagnosisand TABLE4. AdverseEventsofAntibioticsUsedFrequentlytoTreatUTI 39,49,58 – 65,67,74,82 – 86 AntibioticRateofAEsTypeofAEsConsiderations Nitrofurantoin5% – 34% € Commonsideeffects:nausea,headache € AvoiduseifCrCl0mL/min € Decreasedefficacy € Increasedriskoftoxicity € Pulmonaryfibrosis,hepatotoxicityrisk withlong-termuse* TMP-SMX1.4% – 38% € Commonsideeffects:rash,urticaria, nausea,vomiting,hematologic € HyperkalemiaandAKImorelikelyifTMP-SMXuse, elevatedbaselineCr,takingACEinhibitorsand potassiumsupplements* € Hemolysisrare,canoccurinpatientswithG6PDdeficiency* Fosfomycin5.3% – 8% € Commonsideeffects:diarrhea, vaginitis,nausea,headache € Half-lifeofsingledose30 – 40h € Seriousadverseeventsrare Ciprofloxacin4% – 28% € Commonsideeffects:nausea,vomiting, diarrhea,headache,drowsiness,insomnia € Tendinopathy,tendonrupture € Myastheniagravisexacerbation € Peripheralneuropathy € QTintervalprolongation € Riskofuseoutweighsbenefitifalternativeavailable € Tendinopathyriskincreasedifage�60y, takingcorticosteroids,andpriorheart,kidney, andlungtransplant  -Lactams10% – 27% € Commonsideeffects:nausea, diarrhea,headache,lightheadedness, rash,urticaria € ComparedwithotherUTIantimicrobials,typically haveinferiorefficacyandmoreadverseeffects € Associatedwithahigherriskofcollateraldamage (selectionforESBL-producing strains,multidrug-resistance S.aureus ,and Clostridiumdifficile colitis) ACE,angiotensin-convertingenzyme;AEs,adverseevents;AKI,acutekidneyinjury;G6PD,glucose-6-phosphatedehydrogenase. TABLE5. RecommendedRegimensforInitial,EmpiricTherapy ofAcuteUTIinWomenwithComplicatingFactors 33,95,103,104 Initialtreatmentuntilcultureresultsareavailabletoguidetherapy (consideronlyiflocalresistance20%) Fluoroquinolone(eg,ciprofloxacinandlevofloxacin) Aminopenicillin(eg,ampicillin)plusa  -lactaminhibitor (eg,clavulanicacid) Cephalosporingroup3a(parenteral;ie,cefotaxime,ceftriaxone, ceftizoxime,cefmenoxime,cefodizime) Aminoglycoside Empiricaltreatmentinseverecasesorinitialfailure Fluoroquinolone(ifnotusedforinitialtherapy) Piperacillinplusa  -lac

8 taminhibitor Cephalosporingroup3b(parent
taminhibitor Cephalosporingroup3b(parenteral;ie,cefoperazone,ceftazidime) Carbanem Notrecommendedforempiricaltreatment Aminopenicillins(ie,ampicillin,amoxicillin,bacampicillin) TMP-SMX Fosfomycintrometamol AdaptedfromGrabe. 33 FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 RecurrentUTIinAdultWomen ©2018WoltersKluwerHealth,Inc.Allrightsreserved. www.fpmrs.net 7 treatmentbecausetheirbacterialisolatesaremorelikelytobere- sistanttovariousantibiotics. 19,33,93,94 Whenempirictherapyofan acuteUTIwithcomplicatingfactorsisinitiated,treatmentshould bereevaluatedonceurinecultureandsensitivityresultsareavail- able. 95 Theinitialselectionofempirictherapyshouldreflectthe patient'sindividualuropathogenhistory,currenttreatment(eg,if currentlyonUTIsuppressionantibiotics),andresponsetoprior therapy. 33,94 – 104 Ifclinicallyreasonable,antimicrobialtherapy shouldbedelayedpendingcultureresultsandorganismsuscepti- bilitysoantimicrobialtreatmentcanbetargetedbasedonthe uropathogenprofile. 95 Table5displaystherecommendedregi- mensforempirictherapyofUTIwithcomplicatingfactors. Pyelonephritis SeveralotherwiseusefulUTIantibioticsarenotrecommended foracutepyelonephritistreatment,includingnitrofurantoinand fosfomycin;TMP-SMXisnotrecommendedforempirictreat- mentbecauseofhighratesofTMP-SMXresistance.Table6dis- playstherecommendedacutepyelonephritistreatmentregimens. Empiricallyinitiatedantibioticsshouldberefinedwhentheurine cultureresultsareavailable. NonantibioticTreatmentsand Nonoral/NonparenteralAntibioticTreatment Ibuprofen — InitialSymptomaticTreatment Ibuprofenmaybeusedasanadjunctforsymptomsofacute bacterialcystis.However,inwomenwithrUTI,thereisnoevi- dencethatibuprofenshouldbeusedinlieuofanantibiotic(see previousdiscussiononconditionaltreatment). ChineseHerbalMedicine ThereisinsufficientevidencetorecommendChineseherbal medicine(CHM)asrUTItreatment.Theherbalproductsusedin CHM(upto10 – 15herbs)haveundergoneinvitrostudiesshow- ingbiologicplausibilityforrUTItreatmentandclinicalefficacy instudies.A2015Cochranesystematicreviewcomparedstudies ofCHMvsplacebo,CHMvsantibiotics,andCHMplusantibi- oticsvsantibioticsalone. 113 Thesystematicreviewwaslimited byasmallnumber(7)ofstudies,smallsamplesizes,studydesign problems,andanoverallhighbiasrisk.Despitetheselimitations, theauthorsoftheCochranereviewconcludedthatCHMmaybe beneficialforrUTItreatmentduringanacuteepisode(eitheras anindependentorasanadjuncttherapy)andmayreducerUTI forupto6monthsaftertreatment. TABLE6. RecommendedAcutePyelonephritisTreatmentRegimens 33,39,57,60,104 – 112 AntibioticsDailyDoseDurationofTherapy Oralregimensinpatientsnotrequiringhospitalization Ciprofloxacin500 – 750mgBID7 – 10d Levofloxacin500mgQD7 – 10d Levofloxacin750mgQD5d Alternatives Cefpodoxime200mgBID10d Ceftibuten400mgQD10d Limitedtopathogenswithknownsusceptibility(notforinitialempirictherapy) TMP-SMX160/800mgBID14d Amoxicillin-clavulanicacid* † 0.5/0.125gTID14d Antibiotics DailyDose Empiricalparenteralregimenforpatientsrequiringhospitalization Ciprofloxacin 400mgBID Levofloxacin250 – 500mgQD Levofloxacin 750mgQD Alternatives Cefotaxime* 2gTID Ceftriaxone 1 – 2gQD Ceftazidime* 1 – 2gTID Cefepime 1 – 2gBID Amoxicillin-clavulanicacid* † 1.5gTID Piperacillin/tazobactam2.5 – 4.5gTID Gentamicin* 5mg/kgQD Ertapenem 1gQD Imipenem/cilastin0.5/0.5gTID Meropenem 1gTID Doripenem 0.5gTID AdaptedfromGrabe. 33 *Notstudiedasmonotherapyforacuteuncomplicatedpyelonephritis. † Mainlyforgram-positivepathogens. BID,twiceaday;QD,4timesaday;TID,3timesaday. Brubakeretal FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 8 www.fpmrs.net ©2018WoltersKluwerHealth,Inc.Allrightsreserved. IntravesicalInstillations AntibioticBladderIrrigation Antibioticirrigationofthebladderforprophylaxisand/or treatmentprovidessomepotentialadvantagesoveroralandparen- teralroutes.Theseincludedirectdrugdeliverytothesiteofinfec- tionandbypassofgastrointestinaltractwhichavoidscollateral consequencesandsideeffectssuchasgastrointestinalupset. Gentamicinhasbeentheantibioticmoststudiedforbladder irrigation. 114 – 116 Therehavebeennorandomizedcontrolledtrials performedtodate,andallreportshavebeencaseseriesinindivid- ualswithcomplicatedUTIs.Reportshaveincludedfindingsfrom invitro,animal,andhumanstudies.Bladderinstillationregimens haveincludedgentamicinsolutionswithconcentrationsranging from40 – 80mggentamicinwith50mLnormalsaline;instillation volumesof30to60mLwithatleasta1-hourorovernightdwell havebeenrecommended.Noelevatedserumgentamicinlevels wererecorded,andallstudiesreportedameaningfulreduction inUTIswhileinstillationswereperformed.Specialistsmayuse thistherapyinselectpatients,despitethelackofevidencefrom robustcomparisonstudies.Limitedcurrentevidencesupports thesafetyofgentamicinbladderinstillations. Colistin Colistinisapolymyxinmoleculethatdamagesthelipopoly- saccharidecomponentofgram-negativebacteria,leadingtoin- creasedmembranepermeabilityandeventualcelldeath. 117,118 Giuaetal 118 reportedintravesicalcolistinusein3different criticallyillpatientsw ithmultidrug-resistant Acinetobacter . Theintravesicaltreatmentregimenwas100,000UIcolistin in50mLnormalsaline3timesdailyfor90minutesfor7days (2patients)and2days(1patient).All3patientsweresuccess- fullytreated.Althoughtherearenotsufficientda

9 tatorecom- mendthistreatment,itmaybecons
tatorecom- mendthistreatment,itmaybeconsideredinapatientwho hasverylimitedtreatmentoptions. PREVENTION Thegoalofprophylaxisistopreventorsuppresssubsequent infections.Althoughthisismostcommonlyaccomplishedwith antibiotics,alternativenonantibioticoptionsexistaswell. AntibioticProphylaxis BoththeEuropeanAssociationofUrologyandtheSociety ofObstetriciansandGynaecologistsofCanadarecommenden- suringanegativeurineculturebeforestartingprophylacticantibi- otics. 32 Table7displaysrecommendedpostcoitalandcontinuous antibioticregimens.Postcoitalprophylaxisshouldbeofferedto womenwhohaveUTIstemporallyrelatedtosexualintercourse. Thesewomenwilltakeasingledoseofanantimicrobialagentim- mediatelyafterintercourse. 6 Postcoitaltherapydecreasedrecur- renceratescomparedwithplacebo(0.3vs3.6patient-years, P =0.001)andwasequallyasefficaciousascontinuousdaily therapy. 44,119 Thisstrategyhasdecreasedcosts,likelyfewermed- icationsideeffects,anddecreasedriskofantibioticresistance. 4,119 Withcontinuousprophylaxis,apatienttakesasingle,daily antibioticdose. 6 Comparedwithplacebo,continuousprophylaxis decreasesrecurrencesbyupto95%. 20 Thedurationofthesereg- imensrangesfrom6months(basedonobservationsthatUTIs tendtoclusterandrecurwithin3months)toatleast2years;reg- imenshavebeenextendedto5yearsinsomereports. 96,102,113,131 ACochranesystematicreviewofantibioticsforpreventionof rUTIinnonpregnantwomenfoundthatantibioticsgivencontinu- ouslyfor6to12monthswereconsiderablymoreeffectivethan placeboinpreventingrUTI(RR,0.15;95%CI,0.08 – 0.28). 44 Al- thoughlow-doseprophylaxiswithantibioticsmayinhibitemer- genceofbacteriawhileontherapy,thisinhibitionmaynot extendwhentheantibioticisdiscontinued. 44,132 Severalstudies havefoundthat50%to60%ofwomenbecomereinfectedwithin 3monthsofdiscontinuingprophylaxis, 102,113,133 perhapsduein parttointravesicalbacterialpersistence. 134 – 136 Antibioticprophy- laxismayincreasetheriskofbacterialresistance.Thisdocument supportsreevaluationofcontinuousantibioticprophylaxisat 3monthstodeterminetheefficacyandsideeffects.Antibiotic prophylaxisisrarelycontinuedbeyond6months,althoughit mayhavetoberestartedifUTIsrecur. Estrogen Vaginalestrogenshouldbeusedwheneverpossiblein hypoestrogenicwomenwithrUTIbecauseitclearlydecreases UTIrecurrence.Inarandomized,double-blind,placebo-controlled trialof93postmenopausalwomenassignedtotopicallyapplied TABLE7. RecommendedAntibioticProphylaxisRegimens 20,44,119 – 130 AntibioticRegimensforPrevention DoseUTIsPerYear Continuous Trimethoprimdaily100mg0 – 1.5 Trimethoprim/sulfamethoxazoledaily40mg/200mg0 – 0.2 Trimethoprim/sulfamethoxazoleevery3d40mg/200mg0.1 Nitrofurantoinmonohydrate/macrocrystalsdaily50mg0 – 0.6 Nitrofurantoinmonohydrate/macrocrystalsdaily100mg0 – 0.7 Cephalexindaily125mg0.1 Cephalexindaily250mg0.2 Fosfomycinevery10d3g0.14 Postcoital Trimethoprim/sulfamethoxazole40mg/200mg0.3 Trimethoprim/sulfamethoxazole80mg/400mg0 Nitrofurantoinmonohydrate/macrocrystals50 – 100mg0.1 Cephalexin250mg0.03 AdaptedfromHooton. 20 FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 RecurrentUTIinAdultWomen ©2018WoltersKluwerHealth,Inc.Allrightsreserved. www.fpmrs.net 9 intravaginalestriolcream(0.5mgestriolinvaginalcreamdailyfor 2weeks,followedbytwiceweeklyfor8months)vsplacebo,UTI incidenceinthetreatmentgroupdecreasedsignificantly(0.5vs 5.9episodesperpatient-year).Inaddition,after1monthoftreat- ment,lactobacillusappearedin60%oftheestrogen-treatedgroup andnoneoftheplacebogroup. 137 Inanothermulticenterrandom- izednoncontrolledtrialof108postmenopausalwomenwithrUTI randomizedtovaginalestrogenring(2mgestradiol,1ringfor 12weeks,foratotalof36weeks),thevaginalestrogenringsignif- icantlydecreasedUTIoccurrencesandprolongedthetimetonext occurrence. 138 ACochranereviewofthesestudiesindicatedthat vaginalcreammaybemoreeffectivethanthevaginalring, 88 al- thoughsignificantheterogeneityinthesestudiesprohibitedpooling offindings.Asystematicreviewofvaginalestrogentreatment ofvulvovaginalatrophyfoundmoderate-qualityevidenceofde- creasedUTIriskinwomenwithvaginalatrophyusingvaginales- trogen. 139 Studiescomparingvaginalestrogenandantibioticsare inconclusive. 88,140 – 142 Oralestrogenhasnotbeenshowntobeef- fectiveandshouldnotbeusedforrUTIprevention. MethenamineSalts A2012Cochranereviewreportedevidencethatmethena- minehippuratemaybeeffectiveforpreventingUTI,specifically whenusedforshort-termprophylaxis.Methenaminesaltsarecon- vertedintheurinetoammoniaandformaldehyde;formaldehyde isbacteriostaticanddoesnotinduceresistance.Inaddition,me- thenaminehippuratehasanacceptableside-effectprofilewith lowreportedadverseevents. 143,144 Probiotics Thereisnostrongevidencesupportingtheroleofprobiotics inrUTIprevention.Themainorganismsusedinprobioticscome fromlactobacillistrains,whichproduceantimicrobialcompounds thatinhibitpathogenicbacteria. 145 Asystematicreviewof5stud- ies(n=294)focusingonlyonpremenopausalwomenwithcurrent UTIorhistoryofUTIshowedthatusingselectedlactobacillus strainsthatachievevaginalcolonizationcouldpreventrUTI. 146 AlargerCochranereviewthatincluded9probioticintervention studies(n=735)withvariablecontrolsinhealthypremenopausal andpostmenopausalwomenfoundnosignificantreductionin rUTIintheprobioticgroup. 147 However,findingsfromthisstudy wereinconclusivebecausethedatawere

10 derivedfromsmallstud- iesandinconsistent
derivedfromsmallstud- iesandinconsistenttypeanddoseofprobiotics.Robust,placebo- controlledstudiesareneededinpatientswithrUTIusingoptimal probioticagents. Cranberry Thepreponderanceofevidencedoesnotsupportroutineuse ofcranberryproductsinthecareofwomenwithrUTI.Proantho- cynidinspresentincranberriesinhibitbindingoftype1P-fimbriae of E.coli touroepithelialcells.Thestudiesincludedinsystematic reviewsofcranberryarelimitedbymoderateheterogeneity,lack ofconsistencyindosing,andlackofinformationaboutproantho- cynidincontent.Highdropoutratesincranberryjuicegroups suggestanadherencechallenge.Onesystematicreviewof10tri- als(n=1494)comparingcranberryproducts(juice,capsules,or tablets)toplaceboornonplacebocontrolinsusceptiblepopula- tionsconcludedthatcranberryproductsreducedriskofUTIin varioussubpopulationsincludingwomenwithrUTI. 148 Alarger Cochranereview(n=4473)ofplaceboandnonplacebocontrolled trialsusingvariouscranberryproductsinmen,women,andchil- drenwithahistoryofatleast2UTIsintheprevious12months didnotshowareductioninsymptomaticUTIexceptinchil- dren. 149 Amorerecentclinicaltrialof185elderlywomen randomizedtocranberrycapsules(72mg,equivalentto20ozof cranberryjuice)vsplaceboshowednosignificantdifferencein bacteriuriapluspyuria;thestudywasnotpoweredtodetectdiffer- encesinsymptomaticUTI. 28 D -MannoseandM4284 Thereislimitedevidencesupportingroutineuseofthe simplesugar D -mannoseinwomenwithrUTI. D -Mannose, availableoverthecounter,competitivelyinhibits adhesionof UPECtype1fimbria. D -Mannosedecreasesbacterial evelsin animalUTImodels. 150 Inarecentrandomizedclinicaltrialof 308womenwithacuteUTIsandhistoryofrUTIinwhichwomen werefirsttreatedfortheiracuteUTIandthenrandomizedto2gof D -Mannosedailyfor6months,50mgofnitrofurantoindaily,or noprophylaxis,therateofrUTIwas15%,20%,and60%,respec- tively.The D -mannosegrouphadsignificantlyfewersideeffects andequaladherence. 151 AscorbicAcid(VitaminC) AlthoughvitaminChasatheoreticaleffectbasedonacidifi- cationofurine,thereisinsufficientevidencetosupportitsusefor UTIpreventioninwomenwithrUTI.The2studiesthathaveeval- uatedtheeffectofvitaminChadcontradictoryresults. 152,153 NonantibioticIntravesicalInstillations Nonantibioticintravesicalinstillations,includinghyaluronic acidandchondroitinsulfate,arepromising;however,theydo notyethavesufficientclinicalevidenceforuse. 154 – 157 Thetheory behindtheuseofhyaluronicacidandchondroitinsulfateisthat damagetotheglycosoaminoglycanlayeroftheurotheliumis thoughttoplayakeyroleinuncomplicatedUTI. 158 ImmunoactiveProphylaxis Immunostimulantsandvaccinationsarelikelytoplayafu- tureroleinrUTIprevention,althoughthereisinsufficientevi- dencetorecommendclinicaluseatthistime.OM-89isanoral immunostimulantextractedfrom18differentheat-killedUPEC serotypes.Inasystematicreviewof4studies(n=891),there wasareductioninthemeannumberofUTIbyapproximatelyhalf inthetreatmentgroupscomparedwithplacebowithasimilarrate ofadverseevents.Urovacisavaginalvaccinationthatcontains6 serotypesofUPEC,1strainof Proteusvulgaris , K.pneumoniae , Morganellamorganii ,and E.faecalis .Pooledresultsfrom3small studiessuggestaslightreductioninrUTI(RR,0.81;95%CI, 0.68 – 0.96)butonlyinthegroupsthatreceivedboostertherapy aftertheprimaryimmunization. 159 RECOMMENDATIONS SpecialistsinFPMRShaveakeyroleinthecareofwomen withrUTI.Asresearchonpathophysiologyandbestpractices continuestoinformourunderstandingofrUTI,thesebestprac- ticeswillbeupdated.Keyprinciplesforcurrentcareareaccuracy indiagnosiswiththoughtfuluseofcystoscopyandimagingwhen needed,judicioususeofappropriateantibiotics,andeffective preventionstrategies. Readersareencouragedtoreadtheentirebest-practicedoc- ument.Thefollowinglistshighlightseveralkeyrecommendations ofthesebestpractices: Brubakeretal FemalePelvicMedicine&ReconstructiveSurgery  Volume00,Number00,Month2018 10 www.fpmrs.net ©2018WoltersKluwerHealth,Inc.Allrightsreserved. Diagnosis € ThresholdsforrUTIdiagnosisareatleast2in6monthsor atleast3in12months. € Urineculturebeforeinitiatingantibiotictherapyisrecom- mendedtodocumentrUTIepisodesandguidetreatment. € Urinecultureafterappropriatetherapymayhelpdefine distinctepisodes. AntibioticChoice Antibioticchoiceshouldtakeintoaccountspecificpa- tientfactors(allergies,renalfunction),complicatingfactors,and uropathogensensitivity. ForacutecystitisinwomenwithrUTI, € nitrofurantoinisakeyfirst-lineagent; € fosfomyciniseffective;clinicianmayneedtorequest sensitivitytesting; € TMP-SMXcanalsobeusedifresistanceislessthan20%in thecommunity;and € fluoroquinolonesarenotfirst-linetreatmentofacutecystitis withoutcomplicatingfactors. Prevention € Postcoitalantibioticsuppressioniseffectiveinwomenwith coitallyrelatedrUTI. € Low-dose,dailyantibioticsuppression(3 – 6months)iseffective inwomenwithnoncoitallyrelatedrUTI. € Effectivenonantibioticmeasuresare cessationofspermicides, vaginalestrogeninhypoestrogenicwomen,and methenamine. REFERENCES 1.HaylenBT,LeeJ,HusselbeeS,etal.Recurrenturinarytractinfectionsin womenwithsymptomsofpelvicfloordysfunction. IntUrogynecolJPelvic FloorDysfunct 2009;20(7):837 – 842. 2.ModyL,Juthani-MehtaM.Urinarytractinfectionsinolderwomen:a clinicalreview. JAMA 2014;311(8):844 – 854. 3.GuptaK,TrautnerBW.Diagnosisandmanagementofrecurrenturinarytract infectionsinnon-pregnantwomen. BMJ 2013;346:f3140. 4.DasonS,D

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