Joint report of SBI (Brazilian Society of Infectious Diseases), FEBRASGO (Brazilian Federation of Gynecology and Obstetrics Associations), SBU (Brazilian Society of Urology) and SBPC/ML (Brazilian Society of Clinical Pathology/Laboratory Medicine): recomm

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Joint

report

of

SBI

(Brazilian

Society

of

Infectious

Diseases),

FEBRASGO

(Brazilian

Federation

of

Gynecology

and

Obstetrics

Associations),

SBU

(Brazilian

Society

of

Urology)

and

SBPC/ML

(Brazilian

Society

of

Clinical

Pathology/Laboratory

Medicine):

recommendations

for

the

clinical

management

of

lower

urinary

tract

infections

in

pregnant

and

non-pregnant

women

Patricia

de

Rossi

_,

_Sergio

_Cimerman

_,

_José

_Carlos

_Truzzi

_,

Clóvis

Arns

da

Cunha

_,

_Rosiane

_Mattar

_,

_Marinês

_Dalla

_Valle

_Martino

_,

Maurício

Hachul

_,

_Adagmar

_Andriolo

_,

_José

_Ananias

_Vasconcelos

_Neto

_,

João

Antônio

Pereira-Correia

_,

_Antonia

_M.O.

_Machado

_,

_Ana

_Cristina

_Gales

a_{ConjuntoHospitalardoMandaquiandFederac¸ãoBrasileiradasAssociac¸õesdeGinecologiaeObstetrícia(FEBRASGO),SãoPaulo,SP,} Brazil

b_{InstitutodeInfectologiaEmílioRibas,SãoPaulo,SP,Brazil}

c_{UniversidadeFederaldeSãoPaulo(UNIFESP)andInstitutodoCâncerArnaldoVieiradeCarvalho(IAVC),SãoPaulo,SP,Brazil} d_{UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil}

e_{UniversidadeFederaldeSãoPaulo(UNIFESP),EscolaPaulistadeMedicina(EPM),DepartamentodeObstetrícia,SãoPaulo,SP,Brazil} f_{FaculdadedeCiênciasMédicasdaSantaCasadeSãoPauloandHospitalIsraelitaAlbertEinstein(HIAE),SãoPaulo,SP,Brazil} g_{SociedadeBrasileiradeUrologia(SBU),SãoPaulo,SP,Brazil}

h_{UniversidadeFederaldeSãoPaulo(UNIFESP),EscolaPaulistadeMedicina(EPM),SãoPaulo,SP,Brazil} i_{UniversidadeFederaldoCeará(UFC),Ceará,CE,Brazil}

j_{Servic¸odeUrologiadoHospitaldosServidoresdoEstadodoRiodeJaneiroandDepartamentodeUrologiaFemininadaSociedade} BrasileiradeUrologia(SBU),RiodeJaneiro,RJ,Brazil

k_{UniversidadeFederaldeSãoPaulo(UNIFESP),HospitalSãoPaulo,EscolaPaulistadeMedicina(EPM),SãoPaulo,SP,Brazil} l_{UniversidadeFederaldeSãoPaulo(UNIFESP),EscolaPaulistadeMedicina(EPM),DepartamentodeMedicina,SãoPaulo,SP,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Received1March2020

Accepted1April2020

Availableonline30April2020

a

b

s

t

r

a

c

t

Urinarytractinfection (UTI) isa common conditionin women. There isan increased

concernonreductionofbacterialsusceptibilityresultingfromwronglyprescribing

antimi-crobials.ThispapersummarizestherecommendationsoffourBrazilianmedicalsocieties

(SBI – Brazilian Society of Infectious Diseases, FEBRASGO – Brazilian Federation of

∗ _{Correspondingauthor.}

E-mailaddress:patriciatuti1@gmail.com(P.deRossi).

https://doi.org/10.1016/j.bjid.2020.04.002

1413-8670/©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC

Keywords:

Urinarytractinfection

Women Pregnancy Asymptomaticbacteriuria Cystitis Recurrent Antimicrobials

GynecologyandObstetricsAssociations,SBU–BrazilianSocietyofUrology,andSBPC/ML–

BrazilianSocietyofClinicalPathology/LaboratoryMedicine)onthemanagementofurinary

tractinfectioninwomen.

Asymptomaticbacteriuriashouldbescreenedatleasttwiceduringpregnancy(early

andinthe3rdtrimester).Allcasesofsignificantbacteriuria(≥105_{CFU/mLinmiddlestream}

sample)shouldbetreatedwithantimicrobialsconsideringsafetyandsusceptibilityprofile.

Inwomenwithtypicalsymptomsofcystitis,dipsticksarenotnecessaryfordiagnosis.Urine

culturesshouldbecollectedinpregnantwomen,recurrentUTI,atypicalcases,andifthereis

suspicionofpyelonephritis.Firstlineantimicrobialsforcystitisarefosfomycintrometamol

inasingledoseandnitrofurantoin,100mgevery6hoursforfivedays.Secondlinedrugsare

cefuroximeoramoxicillin-clavulanateforsevendays.Duringpregnancy,amoxicillinand

othercephalosporinsmaybeused,butwithahigherchanceoftherapeuticfailure.

In recurrent UTI, all episodes should be confirmed by urine culture. Treatment

shouldbeinitiatedonlyafterurinesamplingandwiththesameregimensindicatedfor

isolated episodes. Prophylaxis options of recurrent UTIare behavioral measures,

non-antimicrobialandantimicrobialprophylaxis.Vaginalestrogensmayberecommendedfor

postmenopausalwomen.Other non-antimicrobialprophylaxis,includingcranberryand

immunoprophylaxis, have weak evidence supporting their use. Antimicrobial

prophy-laxismaybeofferedasacontinuousorpostcoitalscheme.Inpregnantwomen,options

arecephalexin,250–500mgandnitrofurantoin,100mg(contraindicatedafter37weeksof

pregnancy).Nonpregnantwomenmayusefosfomycintrometamol,3gevery10days,or

nitrofurantoin,100mg(continuousorpostcoital).

©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis

anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Introduction

Urinarytract infection(UTI)isacommon condition.

Annu-ally,itaffectsmorethan10%ofwomen,andmorethan50%

ofwomenwillhaveatleastonesymptomaticepisode

dur-ingtheirlifetime.1_{AfterthefirstepisodeofUTI,24%ofyoung}

womenwillrecurwithinsixmonths,and2%to5%willdevelop

recurrentUTI(rUTI).2,3

There is an increasing concern about the development

ofbacterialresistancecausedbytheuse,generally

inappro-priate,ofantibiotics. Theempiricaluse ofbroad spectrum

antimicrobialsformild infections contributes tothe

selec-tion of increasingly resistant strains – extended-spectrum

␤-lactamase(ESBL)enterobacteria,mostoftenEscherichiacoli,

Klebsiellaspp.,Enterobacterspp.,andKlebsiellapneumoniae

car-bapenemase (KPC) –limiting therapeutic options insevere

caseswithsystemicinfection.4

Thistextaddressesevidence-basedrecommendationson

managementofasymptomaticbacteriuriaandlowerUTIin

nonpregnantandpregnantwomen.

WeconsultedthefollowingGuidelines,Recommendations

andProtocolsofthefollowingSocieties/Associationsand

Gov-ernmentAgencies:

– FEBRASGO(BrazilianFederationofGynecologyand

Obstet-ricsAssociations)5,6

– IDSA(InfectiousDiseasesSocietyofAmerica)7,8

– EAU(EuropeanAssociationofUrology)4

– USPSTF(U.S.PreventiveServicesTaskForce)9

– ACOG (American College of Obstetricians and

Gynecologists)10,11

– NICE(NationalInstituteforHealthand CareExcellence–

UK)12

– Brazil,MinistryofHealth(MS)13

– AUA (American Urologic Association), 2019 – with CUA

(Canadian Urological Association) and SUFU (Society

of Urodynamics, Female Pelvic Medicine & Urogenital

Reconstruction)14

Asymptomatic

bacteriuria

Definition

Asymptomaticbacteriuria(ASB)isthepresenceofoneormore

speciesofbacteriainsignificantamount[≥105_{colony-forming}

units(CFU)/mLinamidstreamurinesampleor≥102_CFU/mL

in a catheterized specimen], regardless ofthe presenceof

pyuria,intheabsenceofsignsorsymptomsofUTI.8

ASB is a common condition in healthy women,

affect-ing1%to5%duringreproductiveyearsand2.8%to8.6%at

postmenopausalage.Ininstitutionalizedelderlywomen,the

prevalenceisashigh as50%.5_{Theconditionisbenign, and}

randomized studies have shown that, except for pregnant

women,theuseofantibioticshasnobenefitswhencompared

tonon-treatment; inaddition,thereisanincreasedriskof

bacterialresistanceandClostridiumdifficileinfection.5

Urinespecimencollectionmustfollowcorrecttechnique

for reliable results.15 _{The samplemust be collected in the}

laboratory,using,wheneverpossible,thefirstvoidurine.

Oth-erwise,urineshould beretainedinthebladder foratleast

2h before collection in order to reduce the occurrence of

repletionisnotrecommended, becauseexcess fluiddilutes

urine,decreasingthecolonycountoryieldingfalsenegative

results.15

GeneralrecommendationsonASB8

1. Donotrequesturinecultureforadultpatientswithout

uri-narysymptoms,exceptintwosituations:

a. Pregnantwomen;

b. Beforeaninvasiveurologicalprocedure.

2. Donotrequesturinecultureinasymptomaticpatientswith

alterationofurinecolor,clarityorodor.

3. Donotrequestpost-treatment urineculturesin

asymp-tomaticpatients,exceptforpregnantwomen.

4. DonottreatASB,eveniftheisolateduropathogenis

mul-tidrugresistant,inthefollowingcases:

a. Elderlywomenwithcognitivedysfunction;

b. Non-pregnanthealthyyoungwomen;

c. Postmenopausalwomen;

d. Diabeticpatients;

e. Patientswithindwellingurethralcatheter;

f. Patientswithspinalcordinjury;

g. Patientswhohavereceivedkidneyorothersolidorgan

transplant;

h. Elective non-urological surgery (e.g., orthopedic

implants);

i. Prior tourological device implantation (only perform

standard perioperativeantimicrobialprophylaxisprior

theprocedure);

j. Pediatricpatients.

In some situations, it is uncertain if there is a

rec-ommendation for or against screening or treating ASB:

high-riskneutropenia(absoluteneutrophilcount<100/mm3_,

≥7days’duration followingchemotherapy) andatthetime

ofindwellingcatheterremoval(mayreducetheriskofUTIin

somepatients).

Asymptomatic

bacteriuria

in

pregnancy

Epidemiology

TheprevalenceofASBduringpregnancyisthesameasthat

innon-pregnantwomen(2%–10%).ASBprogressionto

symp-tomaticUTIoccursinapproximately25%ofpatients.ASBis

associatedwith increasedperinatal morbidity(prematurity

andlowbirthweight).UntreatedASBisrelatedto

pyelonephri-tisinupto40%ofpregnancies;however,withtreatment,this

ratedropsto3%.16,17

Etiology

Proximityofanustoperi-urethrainwomenfavorsinfection

with enterobacteria. More than 80% ofbacterial infections

arecausedbyE.coli,followedbyotherGram-negativestrains

(Klebsiellaspp., Enterobacter spp., Proteusmirabilis). The most

commonGram-positivebacteriaareStaphylococcus

saprophyti-cusandStreptococcusagalactiae(GroupBStreptococcus).18

Asymptomaticbacteriuriainpregnancy–recommendations

1. AllpregnantwomenshouldbescreenedforASBinearly

prenatalcareandatthebeginningofthirdtrimester.In

casesofincreasedriskofinfection(e.g.,diabetesmellitus),

considermorefrequentscreening.

2. ASBisdiagnosedbyurine culturewithsignificant

bac-teriuria(≥105 _{CFU/mLinamidstream urine sampleor}

≥102_{CFU/mLinasamplecollectedbyurethral}

catheteri-zation).

3. All pregnant women with ASB should be treated with

antibiotics.

4. Thechoiceofantimicrobialshouldbebasedonthe

antibi-oticsensitivity profile and its safety during pregnancy

(FDApregnancyriskcategory).

5. RecommendedtreatmentoptionsforASBinpregnancy

are amoxicillin, cephalexin, cefuroxime, fosfomycin

trometamol,andnitrofurantoin(Table1).

6. Therapy duration is fivedays fornitrofurantoin, seven

days for beta-lactams, or a single dose of fosfomycin

trometamol.

7. Acontrolurinecultureshouldbedone1–2weeksafter

theendoftreatmentand,ifpositive,shouldbetreatedas

statedabove.

8. Antimicrobialprophylaxismustbecarriedoutuntillate

pregnancyafterthesecondepisodeofASBor,ifthereis

historyofrUTI,afterthefirstepisodeofASB.

9. Theantibioticmaybeusedinthepostcoitalregimenin

thosepatientswhohaveUTIsrelatedtosexualactivity,or

continuously(atbedtime).

10. Antibiotics recommended for prophylaxis are

nitrofu-rantoin (do not use after 37 weeks of gestation) and

cephalexin(Table2).

Uncomplicated

cystitis

in

women

Definition

Uncomplicatedcystitisisdefinedasanacute,non-recurrent

bladder infection in a healthy, nonpregnant woman

with-out anatomical or functional abnormality of the urinary

tract.19

Etiology

Most cystitis in women are caused by enterobacteria. The

ARESC study, which assessed the etiology and bacterial

susceptibility profile in Brazil and nine European

coun-tries between 2003 and 2006, showed that approximately

three quarters of cystitis in Brazil were caused by E. coli;

Gram-positive species were identified in about 5% of the

cultures.20

Recently(2007–2012),Hisanoetal.analyzedcultureresults

ofwomenwithuncomplicatedcystitisfromaquaternary

hos-pitalinSão Paulo.21 _{Asinthe ARESCstudy,E.coliwas the}

mostprevalentspecies–followed,inoutpatients,byE.

fae-calis and, in emergency room patients, by S. saprophyticus

Table1–RecommendedantibioticsfortreatmentofASBinpregnancy.

Drug Dose Duration Comments

Fosfomycintrometamol 3g Singledose

Nitrofurantoin 100mgq6ha _{5days Donotuseafter37weeksof}

pregnancy

Cephalexin 500mgq6ha _{7days Othercephalosporinsmaybe}

usedatusualdoses

Cefuroxime 250mgq12ha _7days

Amoxicillin 500mgq8ha_or875mgq12ha _{7days TreatmentofchoiceforGroup}

BStreptococcus(GBS, Streptococcusagalactiae)and Enterococcusfaecalis a _{aq6h:every6h;q8h:every8h;q12h:every12h.}

Table2–RecommendedregimensforUTIantimicrobialprophylaxisinpregnancy.a

Drug Dose Comments

Nitrofurantoin 100mg Donotuseafter37weeksofpregnancy

Cephalexin 250–500mg

a _{Continuousorpostcoitalregimen}

75.5 6.4 10 2.7 2.7 1.8 7.3 70.5 2.1 6.4 5 10 3.9 9.3 0 10 20 30 40 50 60 70 80

Escherichia coli Klebsiella pneumoniae

Enterococcus faecalis

Proteus mirabilis Staphylococcus saprophyticus

Streptococcus agalactiae

Other species

%

Uncomplicated Cystitis - Outpatient Clinic Uncomplicated Cystitis - Emergency Room

Fig.1–Etiologydistributionofuncomplicatedcystitisinoutpatientsandemergencyroompatientsinaquaternaryhospital ofSãoPaulo(2007–2012).AdaptedfromHisanoetal.21

Clinicalpresentation

Usually, the patient presents with acute onset of dysuria,

increased urinary frequency, urinary urgency, suprapubic

pain/tenderness,andhematuria.22

The differential diagnosis for uncomplicated cystitis

includespyelonephritis(fever,chills,flankpain,costovertebral

angletenderness,nausea/vomiting)andurethritisbyNeisseria

gonorrhoeae,Chlamydiatrachomatisor Ureaplasmaspp.

Vulvo-vaginalinfectionssuchascandidiasisorgenitalherpesand

irritative/allergicvulvitis may cause dysuriaand should be

ruledout.11,14,22

The appearance of urine (color, odor, or transparency)

shouldneverbeusedasisolatedcriteriafordiagnosisofUTI

orstartantimicrobialtherapy.23

Diagnosis

Clinicalpresentationhashighsensitivityandhighspecificity

fordiagnosisofacutecystitis.Presenceofdysuria,frequency,

hematuria,nocturia,and urgencyallincrease the

probabil-ityofUTI(likelihoodratio–LR>1),whilepresenceofvaginal

dischargedecreasestheprobabilityofUTI(LR<1).24_Inwomen

withoneormoresymptomsofUTI,theprobabilityofinfection

isapproximately50%;ifthepatienthasdysuriaandfrequency

withoutvaginaldischargeorirritation,theprobabilityofUTI

increasestomorethan90%.25

Inpatientswithtypicalpresentation,urinarydipstick

min-imallyincreasesdiagnosticaccuracy;additionally,anegative

resultdoesnotexcludeinfection.4,22 _{Pyuriaisanonspecific}

finding,soitisnotsufficienttoconfirmadiagnosisofaUTIin

theabsenceofsymptoms.6,7

ThegoldstandardforthediagnosisofUTIisapositiveurine

culture.Despitenotbeingindicatedinuncomplicatedcystitis,

urinecultureandantimicrobialsusceptibilitytestshouldbe

performedinpregnantwomen,womenwithsuspectedacute

pyelonephritis,andinrecurrentinfection(duetohigherrisk

ofbacterialresistance).Urinecultureisalsorecommended

inwomenwhopresentwithatypicalsymptoms,therapeutic

Table3–SusceptibilityofuropathogensforantimicrobialsinBrazil.

Antimicrobial ARESCStudy(2008)28 _{Rochaetal.(2012)}29 _{Hisanoetal.(2014)}21

E.coli(%) Allspecies(%) Allspecies(%) E.coli(%)

Fosfomycintrometamol 97.0 94.9 – – Nitrofurantoin 94.3 84.1 87.8 96.8 Ciprofloxacin 89.2 89.0 83.6a _82.3 Amoxicillin-clavulanate 79.8 78.7 – 96.5 Cefuroxime 74.5 75.7 – – Trimethoprim-sulfamethoxazole 54.5 58.4 63.3 62.5 Ampicillin 37.7 33.8 54.6 46.0

AdaptedfromHisanoetal.,21_Naberetal.28_{andRochaetal.}29

a _{Includeslevofloxacin.}

oftreatment),andUTIrecurrencewithinfourweeksoftheend

oftreatment.4,6,10

Treatment

Phenazopyridine,200mg 3times daily forup to 48h, may

be used to relieve moderate to severe dysuria. Choice of

antimicrobial therapy should be guided by spectrum and

local susceptibility patterns of the pathogens, tolerability

and adverse effects, risk ofbacterial resistance,costs, and

availability.4,6

Nitrofurantoin isactive againstE. coli(∼90%ofstrains),

Enterococcus spp., S. aureus, S.saprophyticus, and StrepB (S. agalactiae),whileProteusspp.andPseudomonasspp.are

intrin-sicallyresistanttothisantibiotic.Fosfomycintrometamolis

activeagainstE.coli(includingESBL-producingstrains),

Ente-rococcusspp.,S.aureusandS.epidermidis.Susceptibilitystudies

havedatashowinglimitedactivity offosfomycinagainstS.

saprophyticus.26,27

InARESCstudy,fosfomycintrometamoland

nitrofuran-toinwerethemostactivedrugsagainstbacteriaisolatedfrom

womenwith cystitis(Table 3).28 _{AmongE. coli,}

susceptibil-itywas>90%forbothdrugs(97.0%and94.3%,respectively).

However, overall susceptibility to nitrofurantoin was lower

(84.1%).Thehighestresistancerateswereforampicillinand

trimethoprim-sulfamethoxazole(TMP-SMX).28

AnepidemiologicalstudycarriedoutinthecityofCuritiba,

Brazil evaluated urine cultures from outpatients between

MayandDecember2009.29_{Urinecultureswith≥10}5_CFU/mL

wereconsideredpositiveandsubmittedtoantimicrobial

sus-ceptibilitytesting. Exclusion criteria included fungi, mixed

cultures,age<13yearsold,andinpatientsamples.Inpatients

withmorethanoneurineculture,onlythefirstspecimenwas

consideredforanalysis.29

Fromatotalof67,650urinecultures,12,567werepositive.

Afterapplicationoftheexclusioncriteria,2769sampleswere

excluded, remaining9798urine cultures(8700from female

patients).Nitrofurantoinandfluoroquinoloneswerethemost

activeoral antimicrobials; fosfomycintrometamol was not

tested(Table3).29

Antimicrobial

treatment

Therecommendedantibioticsforuncomplicatedcystitisin

womenarefosfomycintrometamol(3gorally,inasingledose)

and nitrofurantoin (100mg orally, every 6h, for five days).

Thesedrugshaveuniquemechanismsofactionandlow

resis-tancerates.Theyalsopresenthighurinaryconcentrationsand

areactiveagainstESBL-producingbacteria.30

Second-line alternatives are cefuroxime, a

second-generation cephalosporin, and amoxicillin-clavulanate

(Table4).

Fluoroquinolones (FQ – norfloxacin, ciprofloxacin,

lev-ofloxacin) are notrecommended inuncomplicated cystitis

duetoreduceduropathogensusceptibilityanddevelopment

of bacterialresistance. Inaddition, these drugs may cause

severe and debilitating adverse effects, including

tendini-tis/tendonrupture,muscleweakness,peripheralneuropathy,

autonomicandcognitivedysfunction,seizure,dementia,

psy-chiatric disorders,rupture ofaorticaneurysm,arrhythmias

anddysglycemia(changesinglucosemetabolismleadingto

hypo-orhyperglycemia)–conditionsdefinedbytheFDAin

2016asFluoroquinolone-AssociatedDisability(FQAD).31

Similarly,in2019,theEuropeanMedicinesAgency(EMA)

issuedrecommendations restricting FQusedueto therisk

ofdisablingandpotentiallypermanentsideeffects.32

Restric-tionsapply,amongotherthings,totreatingmildormoderate

lower UTI and preventing rUTI. It also recommends

spe-cialcautioninelderlypatients,patientswithkidneydisease,

transplantrecipients,andthoseusingcorticosteroids,dueto

higherriskoftendoninjury.32

Inconclusion,FQmustnotbeusedtotreatcystitis,unless

nootheroptionsareavailable.4,6

Followup

Ifsymptomsresolve(clinicalcure),thereisnoindicationfor

urinecultureaftertreatment–exceptinpregnantwomen.14

Cystitis

in

pregnancy

Cystitisaffects2%ofpregnanciesandareoftenprecededby

untreatedASB.33,34

Asinnonpregnantwomen,thediagnosisofcystitisisbased

onclinicalpresentation.Specifically,thecomplaintofdysuria

mustbevaluedonceurinaryfrequencyandurgencymaybe

presentduringpregnancyintheabsenceofinfection.35,36

Allpatientsmustreceiveantimicrobialtreatment.

When-everpossible,FDAcategoryBdrugsshouldbeused.4,5_Besides

Table4–Recommendedregimensforuncomplicatedcystitisinnonpregnantwomen.

Drug Dose Duration

Recommended(first-line)

Fosfomycintrometamol 3g Singledose

Nitrofurantoin 100mgq6ha _5days

Alternatives(second-line)

Cefuroxime 250mgq12ha _7days

Amoxicillin-clavulanate 500/125mgq8ha_{or875/125mgq12h}a _7days

a _{q6h:every6h;q8h:every8h;q12h:every12h.}

Table5–Therapeuticschemesforcystitisinpregnancy.

Drug Dose Duration Comments

Fosfomycintrometamol 3g Singledose

Nitrofurantoin 100mgq6ha _{5days Donotuseafter37weeksofpregnancy}

Amoxicillin-clavulanate 500/125mgq8ha_{or875/125mgq12h}a _7days

Cefuroxime 250mgq12ha _7days

a _{q6h:every6hs;q8h:every8h;q12h:every12h.}

first-generationcephalosporins(e.g.,cephalexin)maybeused

asalternatives–butwithahigherchanceoftherapeuticfailure

(Table5).4,6,19

Urineculturemustbecollectedpriortoantimicrobialuse

and1–2weeksaftertheendoftreatment.

Antimicrobial prophylaxis must be taken until delivery

afterthe secondepisodeofcystitisor,ifthereishistoryof

rUTI,afterthefirstepisode.Indicatedregimensarethesame

usedforprophylaxisafterASB(Table2).4,5

Incasesofseveredysuria,phenazopyridine(FDAcategory

B)maybeusedatadoseof200mgevery8hforupto48h.37

Uncomplicatedcystitisinwomenandduringpregnancy–

Recommendations

1. Typicalcasesofcystitisdonotrequirefurtherteststo

con-firm the diagnosis.Patients withdysuria and frequency

withoutvaginaldischargeorirritationhave>90%chance

ofUTI.

2. Urine culture should be collected prior to treatment,

including cases with diagnostic doubt or suspected

pyelonephritis.

3. The first-line antimicrobials for cystitis are

nitrofuran-toin and fosfomycin trometamol; alternatives

(second-line drugs) are cefuroxime and amoxicillin-clavulanate.

Cephalosporins or amoxicillin may be used, but with a

higherchanceoftherapeuticfailure.

4. Antimicrobial prophylaxis must be taken until delivery

afterthesecondepisodeofcystitisor,ifthereisahistory

ofrUTI,afterthefirstepisode.

5. Nitrofurantoin or cephalexin,in continued or postcoital

regimens,aredrugsofchoiceforantimicrobialprophylaxis

duringpregnancy.

6. Fluoroquinolones(norfloxacin,ciprofloxacin,levofloxacin)

mustnotbeusedtotreatuncomplicatedcystitisinwomen

orduringpregnancy.

Table6–Age-relatedriskfactorsassociatedwithrUTIin women.

Youngandpremenopausal women

Postmenopausalandelderlywomen

Sexualintercourse HistoryofUTIbefore menopause Spermicideuse Urinaryincontinence Newsexualpartner Atrophicvaginitisdueto

estrogendeficiency MotherwithUTIhistory Cystocele

ChildhoodUTIhistory Post-voidingresidualvolume increase

Urinarycatheterizationand functionalstatusdeterioration ininstitutionalizedelderly AdaptedfromEAUGuidelines.4

Recurrent

urinary

tract

infection

Definition

Recurrenturinary tract infection(rUTI)is definedas

recur-renceofatleastthreeUTIsinoneyearoratleasttwoepisodes

insixmonths.4Ineachepisodethepatientshouldhaveacute

onsetsymptomsandbacteriuria≥102_{CFU/mLinamidstream}

voidurinesample.14

Epidemiologyandriskfactors

Anestimated25%ofwomenwhohavehadanUTIwilldevelop

anewepisodewithinsixmonths.38 _{Severalriskfactorsfor}

recurrence have been identified in premenopausal young

Table7–BehavioralmodificationsforpreventionofrUTI.

Wipingfromfronttobackafterdefecation Liberalfluidintake

Donotpostponeurination Postcoitalvoiding Avoidvaginaldouching

Donotwearocclusiveunderwear/clothes AdaptedfromEAUGuidelines.4

Etiology

TheproportionofUTIcausedbynon-E.colispeciesishigher

inrUTIin comparisontosporadicinfections.There isalso

anincreasedfrequencyofresistanturopathogensinrecurrent

episodes.39

Evaluation

Diagnostic evaluation requires a comprehensive patient

historyandphysicalexamination.Urinarytractexams

(cys-toscopy, kidney and bladder ultrasound) are not required

in women with rUTI – except when associatedconditions

suchasnephrolithiasis,obstruction,orurothelialcancerare

suspected.4,14

Allepisodesofcystitismustbeconfirmedbyurineculture.

Iftheinitialsampleissuspectedofcontamination,consider

collectinganewspecimen–ifnecessary(suchasinpatients

withurinaryincontinence),byurethralcatheterization.14

Periodicurineculturesarenotrecommended in

asymp-tomaticpatients,andantibioticsshouldnotbeprescribedin

casesofbacteriuria(“don’tscreen,don’ttreat”).14

Treatment

Acuteepisodesmustbetreatedempirically–withfosfomycin

trometamolandnitrofurantoinasfirstchoice–,considering

resultsofpreviouscultures,recentuseofantibioticsandthe

localbacterial resistancepattern. Short-term regimens (≤7

days)shouldbepreferred.4,14

Infectionscausedbybacteriaresistanttooralantibiotics

shouldbetreatedwithparenteralantibioticsfortheshortest

timepossible(ideally,lessthansevendays).14

ProphylaxisofnewepisodesofUTI

Strategies for prophylaxis of new episodes of UTI include

behavioral measures, non-antimicrobial prophylaxis and

antimicrobialprophylaxis.RiskfactorsforrUTImustbe

iden-tifiedandtreated–forexample,changingthecontraceptive

method(stoppingspermicideuse)andtreatingthecauseof

significantresidualurine.4,14

Behavioral

measures

Patients should be counseled on behavioral changes that

mayreducethe riskofUTI (Table 7).4,6,14,19 _{Althoughthese}

measureshavenotshownreductionintheriskofrUTIin

well-designedprospectivestudies,it isreasonabletoofferthem

topatientsbecauseoftheirlowriskand theirpotentialfor

effectiveness.19

Non-antimicrobial

prophylaxis

Vaginalestrogen

The use of vaginal (but not oral) estrogen reduces the

risk of rUTI and may be offered to all postmenopausal

patients.4,6,14 _{The options currently available in Brazil are}

estriol(1mg/gvaginalcream)andpromestriene(10mg/g

vagi-nalcreamand10mgvaginalcapsules).Thetreatmentwith

estriol is started with 0.5mg (1 full applicator) daily for

two weeks followed by the same dose twice a week.40,41

Theinitialdoseforpromestrieneis10mg(1 fullapplicator

or onevaginal capsule) for20 consecutive days, then two

times/week.42

Estrogenbyvaginalroutehaslowsystemicabsorptionand

doesnotrequireassociationwithprogestogensfor

endome-trialprotection.14,43 _{Treatmentmaybecontinuedasneeded}

withnotimelimit.20_{Thereisnosafetydataforvaginal}

estro-genuseinpatientsathighriskforendometrialcancer.Cases

ofbreastcancermustbeindividualized,withpreferenceto

promestriene.36

Cranberry

The use ofcranberry in rUTI is based on the presenceof

proanthocyanidinA,whichpreventsbacterialfimbria

adher-ence totheurothelium.Clinicalstudieswithcranberryuse

different doses and presentations, including juices,

cap-sules, and tablets, making it difficult to compare efficacy

results.4,6,14

There isnoconsensusontheindicationofcranberryas

rUTIprophylaxis: thereare guidelinesthatadvocateits use

(without specifying which formulation),14 _{but others that}

donotrecommendit duetothelackofconsistentefficacy

results.4,6

Becauseofthelackofsolidevidenceofclinicalbenefit,the

useofcranberryforrUTIprophylaxisinwomenisnotstrongly

recommended. Immunoprophylaxis

OM-89isanoralimmunotherapymadewithfragmentsof18

strainsofE.coli.Thisimmunoactivecompoundis

adminis-teredincapsulesfor90consecutivedays.4

Immunoprophylaxisisnotaconsensusintheliterature.

This medication is recommended for rUTI prevention in

women byEAU and FEBRASGO, but notbyAUA/CUA/SUFU

guidelines.4,6,14

Althoughtherearesomerandomizedclinicaltrialsusing

OM-89withpositiveresults,weconsiderthatthereisno

scien-tificevidenceenoughtostronglyrecommendtheuseofOM-89

Table8–RecommendedantimicrobialsforrUTIprophylaxisinnonpregnantwomen.

Drug Posology(continuous) Posology(postcoital)

Fosfomycintrometamol 3gevery10days –

Nitrofurantoin 100mg/day 100mg

Other

modalities

of

non-antimicrobial

prophylaxis

WedonotrecommendotherformstopreventrUTI,

includ-ing:

d-Mannose4,14;

Intravesicalinstillationofhyaluronicacidwithchondroitin

sulfate4,14_;

Methenamine14_;

Herbaltherapies14_;

Pelvicfloorbiofeedback14_;

Probiotics(Lactobacillusspp.).4

Antimicrobial

prophylaxis

Afterdiscussingrisks,benefits,andalternatives,womenofall

agesmaybeofferedantimicrobialrUTIprophylaxis.3,14,25

Antimicrobials are effective in reducing rUTI, but their

disadvantages include the risk of adverse effects and the

developmentofbacterialresistance.4,6,14

Therearetwostrategiesfortheprophylacticuseof

antimi-crobials: continuous or postcoital administration.4,6,14 _The

continuousregimenconsistsofdailyadministrationat

bed-time.ForwomenthatnoticethattheirUTIepisodesarerelated

tosexualactivity,the antimicrobialistaken beforeor after

sexualintercourse.This strategyhasthe advantageofless

exposuretoantibioticsandfewersideeffects.14

Prophylaxismay be givenfrom sixmonthstooneyear,

emphasizingthattheprophylacticeffectisonlyobserved

dur-inguse.4,6,14

RecommendedregimensarelistedinTable8;thereisno

advantageinperiodicallychangingtheantibiotic.12,17

AlthoughFQhavebeenusedforprophylaxis,theyareno

longerrecommendedbecausetherisksoftheirusein

uncom-plicatedUTIsoutweighthebenefits.25

Prolongeduseofnitrofurantoin(>14days)maycause

pneu-monitis;theriskincreaseswithageandishigherinwomen

withrenaldysfunction.44–46

Recurrenturinarytractinfection–recommendations

1. Patients withrUTI(twoor moreepisodesofUTIin six

monthsorthreeormoreinoneyear)shouldbeevaluated

withacomprehensivehistoryandphysicalexamination.

2. AllsuspectedrUTIepisodesmustbeconfirmedbyurine

culture.

3. Routineworkupoftheurinarytract(e.g.cystoscopy,

uri-narytract ultrasound)isnotrecommended incasesof

rUTIwithoutriskfactors.

4. Periodicurineculturesarenotrecommendedin

asymp-tomaticpatients,andantibioticsshouldnotbeprescribed

incasesofbacteriuria(“don’tscreen,don’ttreat”).

5. InacuteepisodesinrUTIpatients,empiricaltreatment

mustbeinitiatedwiththe usualcystitisregimensafter

urineculturesampling(Table5).

6. Acuteepisodescausedbybacteriaresistanttooral

antibi-oticsshouldbetreatedwithparenteralantibioticsforthe

shortesttimepossible.

7. RiskfactorsforrUTImustbeidentifiedandtreated.

8. Behavioral measures should be recommended to all

patients.

9. Vaginal estrogens(estriol or promestriene), if not

con-traindicated,maybeofferedtopostmenopausalwomen.

Thereisnoneedtoassociateprogestogensfor

endome-trialprotection.

10. There is no scientific evidence enough to recommend

cranberryorOM-89forrUTIprophylaxisandtheirusemay

bediscussedindividuallywitheachpatient.

11. d-Mannose,intravesicalinstillation,methenamine,

pro-biotics,herbaltherapiesandbiofeedbackarenot

recom-mendedasprophylaxis.

12. After discussion of risks and benefits, antimicrobial

prophylaxiswitheitherfosfomycintrometamolor

nitro-furantoinmaybeofferedonacontinuousorpostcoital

regimenforsixto12months(Table8).

Conflicts

of

interest

PatriciadeRossi:speaker(Zambon)

SergioCimerman:noconflictofinterest

JoséCarlosTruzzi:speaker(Zambon)

Clovis Arns da Cunha: consultation fee/participation in

advisoryboard,clinicalresearch,speaker:AstraZeneca,Bayer,

CerexaInc.,Eurofarma,Janssen,MSD,Novartis,Pfizer/Wyeth,

Sanofi-Aventis,Zambon

RosianeMattar:noconflictofinterest

MarinêsDallaValleMartino:noconflictofinterest

MaurícioHachul:noconflictofinterest

AdagmarAdriolo:noconflictofinterest

JoséAnaniasVasconcelosNeto:noconflictofinterest

JoãoAntonioPereira-Correia:noconflictofinterest

AntoniaM.O.Machado:noconflictofinterest

AnaCristinaGales:consultationfee/participationin

advi-sory board, speaker: Abbott, Cristália, InfectoPharm, MSD,

Pfizer,Zambon

r

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