26/10/2015 Acuteuncomplicatedcystitisandpyelonephritisinwomen

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Acuteuncomplicatedcystitisandpyelonephritisinwomen

Authors SectionEditor DeputyEditor

ThomasMHooton,MD StephenBCalderwood,MD AllysonBloom,MD
KalpanaGupta,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Aug04,2014.
INTRODUCTIONAcutecystitisreferstoinfectionofthebladder(lowerurinarytract)itcanoccuraloneor
inconjunctionwithpyelonephritis(infectionofthekidneytheupperurinarytract)[1].

Mostepisodesofcystitisandpyelonephritisaregenerallyconsideredtobeuncomplicatedinotherwisehealthy
nonpregnantadultwomen.Acomplicatedurinarytractinfection,whetherlocalizedtotheloweroruppertract,is
associatedwithanunderlyingconditionthatincreasestheriskofinfectionoroffailingtherapy(suchas
obstruction,anatomicabnormality,urologicdysfunction,oramultiplyresistanturopathogen).

Issuesrelatedtoacuteuncomplicatedcystitisandpyelonephritisinwomenwillbereviewedhere.Issues
relatedtourinarytractinfectionsinmenandacutecomplicatedurinarytractinfectionsarediscussed
separately.(See"Acutecomplicatedcystitisandpyelonephritis"and"Acuteuncomplicatedcystitisand
pyelonephritisinmen".)

EPIDEMIOLOGYAmongsexuallyactiveyoungwomen,theincidenceofsymptomaticurinarytractinfection
(UTI)ishighinoneuniversitycohortof796women,theincidencewas0.5to0.7UTIsperpersonyear[2].
Riskfactorsincluderecentsexualintercourse,recentspermicideuse,andahistoryofurinarytractinfection
[2,3].

Cystitisalsooccursinpostmenopausalwomen.Inaprospectivecohortstudyof1017postmenopausalwomen
followedfortwoyears,theestimatedincidenceofcultureconfirmedacutecystitiswas0.07episodesper
personperyear[4].

Acutepyelonephritisislesscommonthanacutecystitisinonereviewincludingover3200patientswithafirst
episodeofacutepyelonephritis,theannualincidenceofacutepyelonephritiswas12to13casesper10,000
women[5].

PATHOGENESISThepathogenesisofurinarytractinfectioninwomenbeginswithcolonizationofthe
vaginalintroitusbyuropathogensfromthefecalflora,followedbyascensionviatheurethraintothebladder.
Pyelonephritisdevelopswhenpathogensascendtothekidneysviatheureters.Hostandmicrobialfactorsthat
underlieprogressionfrombladdertokidneyinfectionrequirefurtherinvestigation.

Pyelonephritiscanalsobecausedbyseedingofthekidneysfrombacteremia.Itispossiblethatsomecases
ofpyelonephritisareassociatedwithseedingofthekidneysfrombacteriainthelymphatics.

MICROBIOLOGYThemicrobialspectrumofuncomplicatedcystitisandpyelonephritisinwomenconsists
mainlyofEscherichiacoli(75to95percent),withoccasionalotherspeciesofEnterobacteriaceae,suchas
ProteusmirabilisandKlebsiellapneumoniae,andotherbacteriasuchasStaphylococcussaprophyticus[5,6].
OthergramnegativeandgrampositivespeciesarerarelyisolatedinuncomplicatedUTIs.Therefore,local
antimicrobialsusceptibilitypatternsofE.coliinparticularshouldbeconsideredinempiricantimicrobial
selectionforuncomplicatedUTIs.

Amongotherwisehealthynonpregnantwomen,theisolationoforganismssuchaslactobacilli,enterococci,
GroupBstreptococci,andcoagulasenegativestaphylococciotherthanS.saprophyticusfromvoidedurine
mostcommonlyrepresentscontaminationoftheurinespecimen[7,8].Thisissupportedbyastudyof202
premenopausal,nonpregnantwomenwhopresentedwithatleasttwosymptomsofacutecystitis,collecteda
midstream,cleancatchurine,andsubsequentlyunderwenturethralcatheterizationtocollectabladderurine
specimen[9].TherewashighconcordancebetweengrowthonvoidedandcatheterizedspecimensforE.coli,
evenatcountsaslowas10CFU/mL,K.pneumoniae,andS.saprophyticus.Incontrast,enterococciand
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GroupBstreptococciwereisolatedfrom20and25voidedspecimens,respectively,butonlyfromtwo
correspondingcatheterizedspecimenseach.Inthemajorityofspecimenswiththeseorganisms,growthwas
<104CFU/mL,andE.coliwasalsoisolated.ThesedatasuggestthatenterococciandgroupBstreptococci
onlyrarelycausecystitis.

However,itmaybeappropriatetoconsidersuchorganismslikelycausativeagentsinsymptomaticwomen
whenfoundinvoidedmidstreamurineathighcountsandwithpuregrowth.

AntimicrobialresistanceThereisconsiderablegeographicvariabilityamongE.coliforinvitro
susceptibility.Infourlargestudies,resistancerateswerehigherinUSmedicalcentersthaninCanadian
medicalcenters,andhigherinPortugalandSpainthanotherEuropeancountries[1013].Ingeneral,resistance
rates>20percentwerereportedinallregionsforampicillin,andinmanyregionsfortrimethoprim(withor
withoutsulfamethoxazole).Fluoroquinoloneresistancerateswere<10percentinmostpartsofNorthAmerica
andEurope,buttherewasacleartrendforincreasingresistanceovertime[1015].Infact,inasubsequent
studyofE.coliurinaryisolatesfromoutpatientsintheUnitedStates,resistanceratestociprofloxacinwere
showntoincreasefrom3to17percentbetween2000and2010amongthepopulationexamined[14].More
specifically,inapopulationbasedstudyofover5000E.coliurinaryisolatescollectedinMinnesotabetween
2005and2009,theincidenceofbacteriuriawithisolatesresistanttofluoroquinolonesand/ortrimethoprim
sulfamethoxazoleincreasedsignificantlyamongelderlypatientsandthosewithcommunityassociatedisolates
butnotamongnosocomialorhealthcareassociatedcases[15].SuchdatasuggestthattoaccuratelypredictE.
coliresistancerates,cliniciansshoulduseantibiogramsthatarestratifiedbypatientageandlocationof
infectiononset.

However,passivelaboratorybasedsurveillancemethodstendtooverestimatetrueresistanceratessincethey
areskewedbyurineculturesobtainedfrompatientswhomayhavefailedinitialtherapyorwhohavespecific
riskfactorsforresistance,suchasrecenttravelorantimicrobialuse[1618].

Resistanceratesforfirstandsecondgenerationoralcephalosporinsandamoxicillinclavulanicacidare
regionallyvariablebutgenerally<10percent.Nitrofurantoin,fosfomycin,andmecillinam(notavailableinthe
UnitedStates)hadgoodinvitroactivityinallcountriesinvestigated[1013].Thesepatternssuggestthese
threelastagentsareappropriateantimicrobialsforempirictherapyinmostregions.Ongoingmonitoringof
resistanceisnecessaryforoptimizationofempirictherapy.(See'Treatment'below.)

Trimethoprimsulfamethoxazoleistheagentforwhichtherearethemostdatatoguideclinicaluse.Instudies
evaluatingepidemiologicalpredictorsofresistance,theuseofTMPSMXintheprecedingthreetosixmonths
andtravel,particularlyinternationaltravel,wereindependentriskfactorsforTMPSMXresistanceinwomen
withacuteuncomplicatedcystitis[1922].Inaddition,clinical,invitro,andmathematicalmodelingstudieshave
suggesteda20percentresistanceprevalenceasthethresholdatwhichTMPSMXshouldnotbeusedfor
treatmentofacutecystitis[23,24].(See'Cystitis'below.)

Forotherantimicrobialagents,thereareinsufficientdatatodeterminetheresistancelevelsatwhichthe
likelihoodoffailureoutweighsthepotentialbenefitsthedecisiondependsonindividualpractitionerdiscretion.
Inaddition,itisimportantforclinicianstounderstandthatlocalresistanceratesreportedinhospital
antibiogramsareoftenskewedbyculturesofsamplesobtainedfrominpatientsorthosewithcomplicated
infectionandmaynotaccuratelypredictsusceptibilitiesinwomenwithuncomplicatedcommunityacquired
infection,inwhomresistanceratestendtobelower[25,26].

Infectionscausedbyextendedspectrumbetalactamase(ESBL)producingstrainsareincreasinginnumber,
eveninthesettingofuncomplicatedurinarytractinfection[2729].

CLINICALMANIFESTATIONSClinicalmanifestationsofcystitisconsistofdysuria,frequency,urgency,
suprapubicpain,and/orhematuria[30].Symptomsofcystitiscanbesubtleintheveryyoungandveryold.

Clinicalmanifestationsofpyelonephritisconsistoftheabovesymptoms(symptomsofcystitismayormaynot
bepresent)togetherwithfever(>38C),chills,flankpain,costovertebralangletenderness,and
nausea/vomiting[31].Insomecases,thepresentationmaymimicpelvicinflammatorydisease.Rarely,
patientswithacutepyelonephritispresentwithsepsis,multipleorgansystemdysfunction,shock,and/oracute
renalfailure.

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DIAGNOSISTheclinicaldiagnosisofuncomplicatedcystitisorpyelonephritisismadeinapatientwhohas
consistentsignsandsymptomsofurinarytractinfectionsandissupportedbylaboratoryevidenceofpyuria
and/orbacteriuria.Assessmentbeginswiththeclinicalhistory,guidedbytheclinicalmanifestationsabove.
Physicalexaminationisoftennotnecessaryfordiagnosisinwomenwithtypicalsymptomsofcystitis,butif
performed,shouldincludeassessmentforfever,costovertebralangletenderness,andabdominalexamination.
Apelvicexaminationisindicatediffactorssuggestingvaginitisorurethritisarepresent.Pregnancytestingmay
alsobeappropriate.

Laboratorydiagnostictoolsconsistofurinalysis(eitherbymicroscopyorbydipstick)andurineculturewith
susceptibilitydata.Inhealthyambulatorywomen,laboratoryevaluationisoftennotnecessarytomakethe
diagnosisofuncomplicatedcystitis.Urinalysiscanbeusefultosupportthediagnosisiftheclinical
presentationisnottypicalastheabsenceofpyuriasuggestsadiagnosisotherthanurinarytractinfection.
Urinecultureishelpfulifthereisreasontosuspectantimicrobialresistance.Wesendurineforbothurinalysis
andcultureinwomenwithsuspectedpyelonephritis.

Imagingstudiesarenotroutinelyrequiredfordiagnosisofacuteuncomplicatedpyelonephritisbutcanbe
helpfulincertaincircumstances.(See"Acutecomplicatedcystitisandpyelonephritis",sectionon
'Radiographicimaging'.)

ClinicalsuspicionInyoungnonpregnantwomen,dysuria,frequency,urgency,suprapubicpain,or
hematuria,particularlyintheabsenceofvaginalsymptoms,arehighlysuggestiveofaurinarytractinfection.
Theprobabilityofcystitisisgreaterthan50percentinwomenwithanysymptomofurinarytractinfectionand
greaterthan90percentinwomenwhohavedysuriaandfrequencywithoutvaginaldischargeorirritation[30].
Thus,urinalysisorcultureusuallyaddlittletothediagnosticarmamentariuminwomenwithtypicalcystitis
symptomsandareoftennotindicatedinsuchcases.

Acuteuncomplicatedpyelonephritisissuggestedbyfevers,chills,flankpain,costovertebralangletenderness,
andnauseaorvomiting,withorwithoutthetypicalsymptomsofcystitis.Insuchcases,wesendurineforboth
urinalysisandculture.(See'Urinalysis'belowand'Urineculture'below.)

Olderwomenmayhaveanumberofnonspecificurinarysymptoms(suchaschronicdysuriaorurinary
incontinence)thatmayconfusethediagnosisofUTI.Asystematicreviewofstudiesevaluatingthediagnosis
ofUTIamongadultsolderthan65yearslivinginthecommunitysuggestedthatsymptomssuchaschronic
urinarynocturia,incontinence,andgeneralsenseoflackofwellbeingwerecommonandnonspecificforUTI,
andshouldthusnotroutinelyprompturinestudies[32].Incontrast,fever,acutedysuria(<oneweekduration),
neworworseningurinaryurgency,newincontinence,frequency,grosshematuria,andsuprapubicor
costovertebralanglepainortendernessaremorediscriminatingsymptomsamongtheelderlythatshould
prompturinestudies.Inaddition,urinestudiesarewarrantedinacognitivelyimpairedpatientwhohas
persistentchangeinmentalstatusandchangeincharacteroftheurinethatisnotresponsivetoother
interventionssuchashydration.

UrinalysisUrinalysisforevaluationofpyuriaisthemostvaluablelaboratorydiagnostictestforUTI.Pyuria
ispresentinalmostallwomenwithacutecystitisorpyelonephritisitsabsencestronglysuggestsan
alternativediagnosis[33,34]or,inapatientwithpyelonephritis,thepresenceofanobstructinglesion[33].
Urinalysisoftenisnotindicatedinwomenwithtypicalsymptomsofacuteuncomplicatedcystitisbutcanbe
helpfulincasesinwhichtheclinicalpresentationisnottypical.

Themostaccuratemethodforassessingpyuriaistoexamineanunspunvoidedmidstreamurinespecimen
withahemocytometeranabnormalresultis10leukocytes/microL[33].Whitebloodcellcastsintheurineare
diagnosticofuppertractinfection.ThepresenceofhematuriaishelpfulsinceitiscommoninthesettingofUTI
butnotinurethritisorvaginitis.Hematuriaisnotapredictorforcomplicatedinfectionanddoesnotwarrant
extendedtherapy.

Dipsticksarecommerciallyavailablestripsthatdetectthepresenceofleukocyteesterase(anenzyme
releasedbyleukocytes,reflectingpyuria)andnitrite(reflectingthepresenceofEnterobacteriaceae,which
converturinarynitratetonitrite):

Leukocyteesterasemaybeusedtodetect>10leukocytesperhighpowerfield(sensitivityof75to96

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percentspecificityof94to98percent)[35].

Thenitritetestisfairlysensitiveandspecificfordetecting10(5)CFUofEnterobacteriaceaepermLof
urine,thoughitlacksadequatesensitivityfordetectionoflowercolonycountsandofotherorganisms,so
negativeresultsshouldbeinterpretedwithcaution[35,36].Falsepositivenitritetestscanoccurwith
substancesthatturntheurinered,suchasthebladderanalgesicphenazopyridineoringestionofbeets.
(See"Urinalysisinthediagnosisofkidneydisease",sectionon'Redtobrownurine'.)

ThedipsticktestismostaccurateforpredictingUTIwhenpositiveforeitherleukocyteesteraseornitrite,
withasensitivityof75percentandaspecificityof82percent[30].However,resultsofthedipsticktest
providelittleusefulinformationwhenthehistoryisstronglysuggestiveofurinarytractinfection,since
evennegativeresultsforbothtestsdonotreliablyruleouttheinfectioninsuchcases.

UrinecultureThecausativeorganismsandtheirantimicrobialsusceptibilityprofilesarefrequently
predictableinwomenwithuncomplicatedUTI,andthusroutineculturesforsuchinfectionsaregenerallynot
necessaryformanagementdecisions.However,giventheincreasingprevalenceofantimicrobialresistance
amonguropathogens,obtainingaurineculturepriortoinitiationoftherapyiswarrantedifsymptomsarenot
characteristicofUTI,ifsymptomspersistorrecurwithinthreemonthsfollowingpriorantimicrobialtherapy,orif
acomplicatedinfectionissuspected[3740].Inaddition,urinecultureandantimicrobialsusceptibilitytestingof
uropathogensshouldbeperformedinallwomenwithacutepyelonephritis.

Ifvoidedurineculturesaresenttothelaboratory,theclinicianshouldaskthelaboratorytoquantifyE.coli,ifit
grows,toatleast102CFU/mLtoimprovesensitivity.Moreover,E.colishouldnotnecessarilybeconsidereda
contaminantifitgrowsinmixedflorasincealmostanygrowthofE.coliinvoidedurinereflectsbladdergrowth
[9].

Growthoforganismsgenerallythoughttobecontaminantsshouldbeconsideredalikelycausativeagentwhen
foundinvoidedmidstreamurineathighcountsandwithpuregrowth.(See'Microbiology'above.)

Issuesrelatedtointerpretationofurineculturecolonycountsarediscussedseparately.(See"Samplingand
evaluationofvoidedurineinthediagnosisofurinarytractinfectioninadults",sectionon'Definitionofa
positiveculture'.)

DIFFERENTIALDIAGNOSISInotherwisehealthywomen,bothinfectiousandnoninfectiousprocesses
cancausesymptomsofdysuria,frequency,urgency,suprapubicpain,and/orhematuria[8].

VaginitisInwomenwithdysuria,thepresenceofvaginaldischargeorodor,pruritus,dyspareunia,and
absenceofurinaryfrequencyorurgencyshouldpromptconsiderationofvaginitis.Causesofvaginitis
includeyeastinfection,trichomoniasis,andbacterialvaginosis.(See"Approachtowomenwith
symptomsofvaginitis".)

UrethritisEvaluationforurethritisiswarrantedinsexuallyactivewomenwithdysuria,particularlythose
withpyuriaonurinalysisbutnobacteriuria.Causesofurethritisinwomenincludechlamydia,gonorrhea,
trichomoniasis,Candidaspecies,herpessimplexvirus,andnoninfectiousirritants,suchasa
contraceptivegel.(See"ClinicalmanifestationsanddiagnosisofChlamydiatrachomatisinfections",
sectionon'Dysuriapyuriasyndromeduetourethritis'.)

StructuralurethralabnormalitiesWomenwithurethraldiverticulaorstricturescanpresentwithdysuria,
frequencyorurgency,andgrossormacroscopichematuria.Althoughtheymayhavepersistentsterile
pyuria,bacteriuriaisnotpresentintheabsenceofaninfection.(See"Urethraldiverticuluminwomen".)

PainfulbladdersyndromeThisisadiagnosisofexclusioninwomenwhohaveongoingdiscomfort
relatedtothebladderwithsymptomsofdysuria,frequency,and/orurgencybutnoevidenceofinfectionor
otheridentifiablecause.(See"Pathogenesis,clinicalfeatures,anddiagnosisofinterstitialcystitis/bladder
painsyndrome".)

PelvicinflammatorydiseaseLowerabdominalorpelvicpainandfeverarethemostcommonclinical
findingsinpatientswithpelvicinflammatorydisease(PID),althoughdysuriamayalsobepresent.The
findingsofmucopurulentendocervicaldischargeorcervicalmotiontendernessonpelvicexaminationare

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stronglysuggestiveofPID.(See"Pelvicinflammatorydisease:Clinicalmanifestationsanddiagnosis".)

NephrolithiasisThemajorityofpatientswithsymptomaticnephrolithiasishaveflankpain/renalcolicin
additiontogrossormicroscopichematuria.Intheabsenceofinfection,feverisunusualinpatientswith
nephrolithiasis.(See"Diagnosisandacutemanagementofsuspectednephrolithiasisinadults".)

TREATMENT

CystitisConsiderationsinselectinganagentfortreatmentofacutecystitisincludeefficacy,riskofadverse
effects,resistancerates,propensitytocauseecologicaladverseeffectsofantimicrobialtherapy(suchas
selectionofdrugresistantorganismsanddevelopmentofcolonizationorinfectionwithmultidrugresistant
organisms),cost,anddrugavailability[1].Noneoftheantimicrobialscurrentlyavailableclearlyoutweighsthe
othersintermsofoptimizingeachofthesefactorsfortreatmentofacutecystitis,andtheoptimalantimicrobial
inoneregionmaybedifferentfromthatinanother.

Appropriateantimicrobialsfortreatmentofacuteuncomplicatedcystitisinwomeninclude[1]:

Nitrofurantoinmonohydrate/macrocrystals(100mgorallytwicedailyfor5days)earlyclinicalefficacy
ratewith5to7dayregimen90to95percentbasedonrandomizedtrials[4145]andminimalresistance
andecologicaladverseeffects.Nitrofurantoinshouldbeavoidedifthereissuspicionforearly
pyelonephritis,andiscontraindicatedwhencreatinineclearanceis<60mL/minute.

Trimethoprimsulfamethoxazole(TMPSMXonedoublestrengthtablet[160/800mg]twicedailyfor3
days)earlyclinicalefficacyratewith3to7dayregimen86to100percentbasedonrandomizedtrials
[41,42,46,47].EmpiricTMPSMXshouldbeavoidediftheprevalenceofresistanceisknowntoexceed
20percent[23,24]orifthepatienthastakenTMPSMXforcystitisinthepreceding3months[19,20],
althoughuseofTMPSMXisacceptableiftheinfectingstrainisknowntobesusceptible.Insome
regionstrimethoprim(100mgtwicedailyforthreedays)isusedinplaceofTMPSMXandisconsidered
equivalent[37].(See'Antimicrobialresistance'above.)

Fosfomycin(3gramssingledose)[43,4850]clinicalefficacyrate91percentfromonerandomizedtrial
[43],butbacterialefficacyinferiorcomparedwithotherfirstlineagents[48]minimalresistanceand
ecologicaladverseeffects.Fosfomycinshouldbeavoidedifthereissuspicionforearlypyelonephritis.

Pivmecillinam(400mgorallytwicedailyfor3to7days)clinicalefficacy55to82percentbasedon
randomizedtrials[51,52]islowerthanotherfirstlineagents,butminimalresistanceandecological
adverseeffects.Pivmecillinamisanextendedgramnegativespectrumpenicillinusedonlyfortreatment
ofUTI.ItisnotavailableintheUnitedStatesbutisanagentofchoiceinmanyNordiccountriesdueto
lowresistanceratesandlowpropagationofresistance[53].Pivmecillinamshouldbeavoidedifthereis
suspicionforearlypyelonephritis.

Theseantibioticoptionsandsuggestedtreatmentdurationsforacuteuncomplicatedcystitisarethesamefor
anyadultwomanwithacuteuncomplicatedcystitis,regardlessofage.Asystematicreviewofstudies
evaluatingtreatmentofcystitisincommunitydwellingadults65yearsofageconcludedthattheoptimal
regimensarethesameasthoserecommendedforyoungeradultsandthatshorterantibioticcourses(3to6
days)resultedinsimilaroutcomesaslongerones(7to14days)[54].

Thechoicebetweentheseagentsshouldbeindividualizedbasedonpatientcircumstances(allergy,tolerability,
compliance),localcommunityresistanceprevalence,availability,cost,andpatientandproviderthresholdfor
failure.Ifthesefactorsprecludeuseoftheaboveantibiotics,fluoroquinolones(ciprofloxacin,levofloxacin,
ofloxacinin3dayregimens)arereasonablealternativeagents,though,whenpossible,fluoroquinolonesshould
bereservedforimportantusesotherthanacutecystitis[55].Multiplerandomizedtrialshavedemonstratedthat
fluoroquinolonesareveryeffectivefortreatmentofacutecystitis[42,52,5662],althoughincreasedresistance
ismitigatingtheusefulnessofthefluoroquinoloneclass.

PopulationbasedstudieshavedocumentedincreasingresistanceofE.coliurinaryisolatestofluoroquinolones
andtrimethoprimsulfamethoxazolesomestudieshavesuggestedthatresistancehasincreasedinparticular
amongelderlypatients[15].Strainsthatproduceextendedspectrumbetalactamases(ESBL)arealso
increasinginfrequency(see'Antimicrobialresistance'above).Nitrofurantoinandfosfomycinareactiveinvitro
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againstESBLproducingstrains[29,63,64].Inacasecontrolstudyincluding113patientswithESBLproducing
E.coliUTIs,noresistancetofosfomycinwasdetectedandclinicalcurerateswerehigh(93percent)[49].In
theUS,resistancetoalloraloptionsisstilluncommonamongoutpatientswithE.colicystitis.Insuchcases,
acarbapenemisthebestoption(eg,ertapenemoncedailyeitherIVorIM).Aninvitrostudydemonstrated
activityofacombinationregimenwithcefdinirandamoxicillinclavulanate[65],buttherearenopublisheddata
onclinicaloutcomeswiththiscombination.

Oralbetalactams(otherthanpivmecillinamdiscussedabove)arelesseffectivethanfluoroquinolonesand
TMPSMX[37,49,62].Acceptablebetalactamagentsincludeamoxicillinclavulanate,cefpodoxime,cefdinir
andcefaclor,fordurationofsevendays[47,61,62].Cefpodoxime(threedayregimen)didnotmeetcriteriafor
noninferioritytociprofloxacin(threedayregimen)forclinicalcureofacuteuncomplicatedcystitisina
randomizedtrial[66].Otherbetalactams,suchascephalexin,arelesswellstudiedbutmaybeacceptablein
certainsettings.Ampicillinoramoxicillinshouldnotbeusedforempirictreatmentgivenpoorefficacyandhigh
prevalenceofresistancetotheseagents[1013,37].

Ifthereisdiagnosticuncertaintyregardingcystitisversusearlypyelonephritis,useofnitrofurantoin,fosfomycin
andpivmecillinamshouldbeavoidedbecausetheydonotachieveadequaterenaltissuelevels[1].

Giventhatcystitisisassociatedwithincreasingantimicrobialresistanceandhasalowriskofprogressionto
invasivedisease,antimicrobialsparingmanagementstrategiesareofincreasinginterest(eg,antiinflammatory
drugsordelayedtreatment),butwarrantfurtherstudy[67,68].

PyelonephritisUrinecultureandsusceptibilitytestingshouldbeperformedinpatientswithknownor
suspectedpyelonephritis,andinitialempirictherapyshouldbetailoredappropriatelyonthebasisofthe
infectingpathogen[1].Theapproachtoempirictherapydependsontheseverityofillness,theprevalenceof
resistantpathogensinthecommunity,andspecifichostfactorssuchasallergyorintolerancehistory[1].

Pyelonephritisisamoreseriousinfectionthancystitistherefore,expectedefficacyofanantimicrobialagentis
ofgreaterimportancethanconcernaboutecologicaladverseeffects(selectionofdrugresistantorganismsand
thedevelopmentofcolonizationorinfectionwithmultidrugresistantorganisms)[1].

Outpatientmanagementisacceptableforpatientswithmildtomoderateillnesswhocanbestabilizedwith
rehydrationandantibioticsinanoutpatientfacilityanddischargedonoralantibioticsunderclosesupervision.In
anemergencydepartmentreportof44patientswithpyelonephritis,forexample,a12hourobservationperiod
withparenteralantibiotictherapy,followedbycompletionofoutpatientoralantibiotics,waseffective
managementfor97percentofpatients[69].Inpatientmanagementiswarrantedinthesettingofsevereillness
withhighfever,pain,andmarkeddebility,inabilitytomaintainoralhydrationortakeoralmedications,
pregnancy,orconcernsaboutpatientcompliance.

OutpatientFluoroquinolonesaretheonlyoralantimicrobialsrecommendedfortheoutpatientempirical
treatmentofacuteuncomplicatedpyelonephritis[1].Althoughfluoroquinolonesremainhighlyeffectivefor
treatmentofpyelonephritiswhentheinfectingpathogenissusceptible,thereisincreasingresistancetothis
drugclassevenamongcommunityuropathogens[14].Sincetimelyuseofanagentwithinvitroactivityis
essentialtotreatpyelonephritisandminimizeprogressionofinfection,thethresholdforselectinganantibiotic
forempiricbroadspectrumtherapyshouldbesetatarelativelylowresistanceprevalence.For
fluoroquinolones,aresistanceprevalenceof10percenthasbeensuggestedbasedonexpertopinion[1].

Thus,forpatientswithmildtomoderatepyelonephritisinwhomthelikelihoodoffluoroquinoloneresistanceis
expectedtobelessthan10percent(ie,thecommunityprevalenceisnotknowntobehigherthan10percent,
therehasbeennotraveltoanareawithendemicresistance>10percent,andtherehasbeennoexposuretoa
fluoroquinoloneinthelastthreetosixmonths),wesuggestafluoroquinoloneforempirictherapy(ciprofloxacin
[500mgorallytwicedailyforsevendaysor1000mgextendedreleaseoncedailyforsevendays]or
levofloxacin[750mgorallyoncedailyforfivetosevendays])[7074].Thiscanbeadministeredwithorwithout
aninitialintravenousdoseofalongactingparenteralantimicrobial(suchasceftriaxone1gramora
consolidated24hourdoseofanaminoglycoside)[70,75].Incontrast,forpatientswithmoresevere
pyelonephritisorriskfactorsforresistance,intravenoustherapywithsuchalongactingparenteralantimicrobial
shouldbeadministereduntilsusceptibilitydataareavailable.Inallcases,subsequenttherapyshouldbe
tailoredbasedonsusceptibilitydata.
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Inthesettingoffluoroquinolonehypersensitivityorknownresistance,otheracceptablechoicesinclude
trimethoprimsulfamethoxazole(160/800mg[onedoublestrengthtablet]twicedaily)oranoralbetalactam,if
theuropathogenisknowntobesusceptible.Ifeitheroftheseagentsisusedintheabsenceofsusceptibility
data,aninitialintravenousdoseofalongactingparenteralantimicrobialshouldbeadministered(suchas
ceftriaxoneoraconsolidated24hourdoseofanaminoglycoside).Patientsunabletotoleratetheseagents(due
tohypersensitivityand/orresistance)maybetreatedwithaztreonam(1gIVevery8to12hours).(See"Dosing
andadministrationofparenteralaminoglycosides",sectionon'Gentamicinandtobramycindosinginadults'.)

Subsequenttherapyshouldbeguidedbysusceptibilitydata.Appropriateoptionsincludeoralciprofloxacin,oral
levofloxacinororaltrimethoprimsulfamethoxazole[7072].Ciprofloxacininasevendayregimenorlevofloxacin
inafivetosevendayregimencanbeusedinmostpatientswithmildtomoderatediseasewhohavearapid
responsetotreatment.ThedurationoftreatmentwithtrimethoprimsulfamethoxazoleapprovedbytheUnited
StatesFoodandDrugadministrationis14days,butclinicalexperiencesuggeststhat7to10daysiseffective
inwomenwhohavearapidresponsetotreatment[7].

Oralbetalactamagentsarelesseffectivethanotheragentsfortreatmentofpyelonephritis[37,76].Ifthe
pathogenissusceptibleandanoralbetalactamagentiscontinued,itshouldbeadministeredforatleast14
days.

Useofnitrofurantoin,fosfomycin,andpivmecillinamshouldbeavoidedinthesettingofpyelonephritisbecause
theydonotachieveadequaterenaltissuelevels[1].

InpatientWomenwithpyelonephritisrequiringhospitalizationshouldbetreatedinitiallywithan
intravenousantimicrobialregimensuchasafluoroquinolone,anaminoglycoside(withorwithoutampicillin),an
extendedspectrumcephalosporin,anextendedspectrumpenicillin,oracarbapenem[7].Thechoicebetween
theseagentsshouldbebasedonlocalresistancedataandtailoredonthebasisofsusceptibilityresults.

Pyelonephritiscausedbyextendedspectrumbetalactamase(ESBL)producingstrainsshouldbetreatedwitha
carbapenem[77,78].EmpiricantibacterialcoverageforESBLproducingorganismsiswarrantedforpatients
presentingwithsepsisinvolvingtheurinarytract[77].(See"Extendedspectrumbetalactamases".)

Patientsinitiallytreatedwithparenteraltherapywhoimproveclinicallyandcantolerateoralfluidsmay
transitiontooralantibiotictherapy.Fluoroquinoloneserumlevelsachievedwithoralandintravenousdosingare
equivalent,andthemodesofdeliveryareequallyeffectiveclinically[79].Regimensanddosingareasoutlined
intheprecedingsection.(See'Outpatient'above.)

Thedurationofantibiotictherapyneednotbeextendedinthesettingofbacteremiaintheabsenceofother
complicatingfactorsthereisnoevidencethatbacteremiaportendsaworseprognosis[79].

FollowupFollowupurineculturesarenotneededinpatientswithacutecystitisorpyelonephritiswhose
symptomsresolveonantibiotics.

Patientswithacutecystitisorpyelonephritiswhohavepersistentsymptomsafter48to72hoursofappropriate
antimicrobialtherapyorrecurrentsymptomswithinafewweeksoftreatmentshouldhaveevaluationfor
complicatedinfectionasdiscussedseparately.Urinecultureshouldberepeatedandempirictreatmentshould
beinitiatedwithanotherantimicrobialagent.(See"Acutecomplicatedcystitisandpyelonephritis".)

SymptomatictherapyClinicalmanifestationsshouldrespondtoantimicrobialtherapywithin48hours.In
theinterim,forsomepatientswithcystitisaurinaryanalgesicsuchasoverthecounteroralphenazopyridine
threetimesdailyasneededmaybeusefultorelievediscomfortduetoseveredysuria.Atwodaycourseis
usuallysufficienttoallowtimeforsymptomaticresponsetoantimicrobialtherapyandminimizeinflammation.
Infact,dysuriaisusuallydiminishedwithinafewhoursafterthestartofantimicrobialtherapy[80].Thisagent
shouldnotbeusedchronicallysinceitmaymaskclinicalsymptomsrequiringclinicalevaluation.

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"
and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoread

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materials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.
Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepth
informationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)

Basicstopics(see"Patientinformation:Urinarytractinfectionsinadults(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Urinarytractinfectionsinadolescentsandadults
(BeyondtheBasics)"and"Patientinformation:Kidneyinfection(pyelonephritis)(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Acutecystitisreferstoinfectionofthebladder(lowerurinarytract)itcanoccuraloneorinconjunction
withpyelonephritis(infectionofthekidneytheupperurinarytract).Cystitisandpyelonephritisare
generallyconsideredtobeuncomplicatedinotherwisehealthynonpregnantadultwomen.Riskfactors
includerecentsexualintercourse,recentspermicideuse,andahistoryofurinarytractinfection.(See
'Epidemiology'above.)

Themicrobialspectrumofuncomplicatedcystitisandpyelonephritisinwomenconsistsmainlyof
Escherichiacoli(75to95percent),withoccasionalotherspeciesofEnterobacteriaceae,suchasProteus
mirabilisandKlebsiellapneumoniae,andotherbacteriasuchasStaphylococcussaprophyticus.(See
'Microbiology'above.)

Clinicalmanifestationsofcystitisconsistofdysuria,frequency,urgency,suprapubicpainand/or
hematuria.Clinicalmanifestationsofpyelonephritisconsistoftheabovesymptoms(symptomsofcystitis
mayormaynotbepresent)togetherwithfever(>38C),chills,flankpain,costovertebralangle
tenderness,andnausea/vomiting.(See'Clinicalmanifestations'above.)

Laboratorydiagnostictoolsconsistofurinalysis(eitherbymicroscopyorbydipstick)andurineculture
withsusceptibilitydata.Imagingstudiesarenotroutinelyrequiredfordiagnosisofacuteuncomplicated
pyelonephritisbutcanbehelpfulincertaincircumstances.(See'Diagnosis'above.)

Fortreatmentofacuteuncomplicatedcystitisinwomen,wesuggestnitrofurantoin(100mgorallytwice
dailyforfivedays),trimethoprimsulfamethoxazole(TMPSMXonedoublestrengthtablet[160/800mg]
twicedailyforthreedays),fosfomycin(3gramssingledose),orpivmecillinam(400mgorallytwicedaily
forthreetosevendays)(Grade2B).TMPSMXshouldbeavoidediftheprevalenceofresistanceis
knowntoexceed20percentorifthepatienthastakenTMPSMXintheprecedingthreemonths,although
itsuseisacceptableiftheinfectingstrainisknowntobesusceptible.Thechoicebetweentheseagents
shouldbeindividualizedbasedonpatientcircumstances(allergy,tolerability,compliance),local
communityresistanceprevalence,availability,andcost.Fluoroquinolonesarereasonablealternative
agents,althoughwhenpossibletheyshouldbereservedforimportantusesotherthanacutecystitis.(See
'Cystitis'above.)

Foroutpatienttreatmentofuncomplicatedpyelonephritiswesuggestciprofloxacin(500mgorallytwice
dailyforsevendaysor1000mgextendedreleaseoncedailyforsevendays)orlevofloxacin(750mg
orallyoncedailyforfivetosevendays)(Grade2B).Thebioavailabilityandurinarypenetrationof
fluoroquinoloneswithoraldosingiscomparabletointravenousdosing.Inwomenwhohavesevere
pyelonephritis,liveinareaswheretheprevalenceoffluoroquinoloneresistanceisknownorsuspectedto
exceed10percent,haveotherriskfactorsforfluoroquinoloneresistanceasdescribedabove,orcannot
tolerateoralfluoroquinolonetherapy,intravenoustherapywithalongactingparenteralantimicrobialsuch
asceftriaxone(1gram)oranaminoglycoside(consolidated24hourdose)shouldbeadministereduntil
susceptibilitydataareavailable.Subsequenttherapyshouldbeguidedbysusceptibilitydata.(See
'Pyelonephritis'aboveand"Dosingandadministrationofparenteralaminoglycosides",sectionon
'Gentamicinandtobramycindosinginadults'.)

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Topic8063Version25.0

Disclosures
Disclosures:ThomasMHooton,MDConsultant/AdvisoryBoards:Cubist[ComplicatedUTI(Ceftolozane/tazobactam)]Vifor
Pharma[UncomplicatedUTI(Immunostimulanturovaxom)].EquityOwnership/StockOptions:FimbrionTherapeutics[Preventionof
UTI(DevelopingmannosidesthatmayeventuallybeusefulinpreventionofUTI)].KalpanaGupta,MD,MPHConsultant/Advisory
Boards:BoehringerIngelheimGmbH[UTI(Empagliflozin)]Paratek[UTI(Omadacycline)]MelintaPharmaceuticals[UTI].StephenB
Calderwood,MDPatentHolder:VaccineTechnologiesInc.[Vaccines(Choleravaccines)].EquityOwnership/StockOptions:
Pulmatrix[Inhaledantimicrobials]PharmAthene[Anthrax(Antiprotectiveantigenmonoclonalantibody)].AllysonBloom,MDNothing
todisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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