urinary tract infections

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urinary tract infections

Recommandations pour la prise en charge des infections urinaires communautaires de l’adulte F. Caron

^a

, T. Galperine

^b

, C. Flateau

^c

, R. Azria

^d

, S. Bonacorsi

^e

, F. Bruyère

^f

, G. Cariou

^g

, E. Clouqueur

^h

, R. Cohen

ⁱ

, T. Doco-Lecompte

^j

, E. Elefant

^k

, K. Faure

^l

, R. Gauzit

^m

, G. Gavazzi

ⁿ

,

L. Lemaitre

^o

, J. Raymond

^p

, E. Senneville

^q

, A. Sotto

^r

, D. Subtil

^s

, C. Trivalle

^t

, A. Merens

^u

, M. Etienne

^a,∗

aMaladiesinfectieuses,groupederecherchesurl’adaptationmicrobienne(EA2656),universitédeNormandie,CHUdeRouen,76000Rouen,France

bInfectionControlProgram,GenevaUniversityHospitals,Switzerland

cImmunologiecliniqueetmaladiesinfectieuses,centrehospitalierHenri-Mondor,94000Créteil,France

dCabinetdemédecinegénérale,95510Vetheuil,France

eServicedemicrobiologie,hôpitalRobert-Debré,universitéParisDiderot,AP–HP,75019Paris,France

fUrologie,CHUdeTours,37000Tours,France

gUrologie,centrehospitalerDiaconesses,75012Paris,France

hGynécologie,CHRUdeLille,59000Lille,France

iNéonatologie,centrehospitalierintercommunaldeCréteil,94000Créteil,France

jMaladiesinfectieuses,hôpitauxuniversitairesdeGenève,Genève,Switzerland

kCentrederéférencesurlesagentstératogènes,hôpitalArmand-Trousseau,GroupehospitalierEst,AP–HP,75012Paris,France

lMaladiesinfectieuses,CHRUdeLille,59000,France

mRéanimation,CHUdeCochin,AP–HP,75014Paris,France

nCliniquedemédecinegériatrique,CHUdeGrenoble-Alpes,38700LaTronche,France

oRadiologie,CHRUdeLille,59000Lille,France

pMicrobiologie,universitéParisDescartes,CHUdeCochin,75014Paris,France

qMaladiesinfectieuses,CHRUdeLille,59000Lille,France

rMaladiesinfectieuses,hôpitaluniversitaireCarémeau,30000Nîmes,France

sGynécologie-obstétrique,CHRULille,59000Lille,France

tGérontologie,hôpitalPaul-Brousse,94800Villejuif,France

uMicrobiologie,hôpitalInter-arméesBegin,94160Saint-Mandé,France Availableonline16May2018

Keywords:Urinarytractcolonization;Urinarytractinfection;Cystitis;Pyelonephritis;Maleurinarytractinfection;Prostatitis;Urosepsis Mots-clés :Colonisationurinaire;Infectionurinaire;Cystite;Pyélonéphrite;Infectionurinairemasculine;Prostatite;Urosepsis

1. Englishversion

1.1. Introduction

The presentupdates tothe guidelines on the management ofadultcommunity-acquiredurinarytractinfections(UTI)was

∗Correspondingauthor.Maladiesinfectieuses,hôpitalC.-Nicolle,CHUde Rouen,1,ruedeGermont,76083Rouencedex,France.

E-mailaddress:manuel.etienne@chu-rouen.fr(M.Etienne).

performed under the aegis of the French InfectiousDiseases Society(FrenchacronymSPILF),byexpertsfromthefollowing specialties:infectiousdiseases,microbiology,urology,primary caremedicine,geriatrics,andradiology.

As per the French National Authority for Health (French acronymHAS)method[1],eachrecommendationwasattributed agrade(A,B,orC)basedonthe levelof scientificevidence providedbyrelatedstudies(Table1).

Whenliteraturedatawaslacking,therecommendationswere drafted on the basis of a consensus achieved by healthcare

https://doi.org/10.1016/j.medmal.2018.03.005

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Table1

Levelofscientificevidenceandstrengthoftherecommendations.

LevelI GradeA

Well-poweredrandomizedandcomparativestudy Meta-analysis

LevelII GradeB

Low-powerrandomizedandcomparativestudy

LevelIII GradeC

Recentnon-randomizedcomparativestudy Cohortstudy

LevelIV GradeC

Comparativetrialwithahistoricalcohort Caseseries

professionals taking into consideration current practices and experts’opinion.

The guidelines were posted on the SPILF website (www.infectiologie.com)in2014(cystitis,pyelonephritis,male UTI)andwerethenupdatedin2015(UTIinpregnancy,useof temocillinandtrimethoprim[TMP]).Thepresentdocumentpro- videsanoverviewofthemainrecommendations,andincludes changesdecidedin2017totakeintoaccountupdatesrelatedto thebacterialresistancetoantibioticsaswellasthemostrecent publications.

1.2. Terminologyandoverallmanagementstrategy

Formerlyknownas asymptomaticbacteriuria,urinarytract colonizationreferstothepresenceofbacteriaintheurinewith- out any associated clinical signs and symptoms and with or withoutassociatedleukocyturia[2].Exceptforpregnantwomen, thereisnothresholdforbacteriuria.

UTIs refer to infections associating clinical (local or non-specific) and biological signs and symptoms (cystitis, pyelonephritis [APNfor acutepyelonephritis], acuteprostati- tis,andotherpresentationsofmaleUTIs.Thepresentdocument onlydealswithacutepresentations(intheinterestofsimplifica- tionandaspercommonlyusedmedicalterms,theterm“acute”

isnotalwaysindicated).Thepresentdocumentfocusesonadult urinary tractinfections andmaybe used with adolescentsas youngas16yearsold.

Whentheurinecultureispositive,thefirststepistodistin- guishacolonizationfromaninfection(Fig.1).

In caseofUTI,onemustthen determinewhetherthe pre- sentationisuncomplicatedoratriskofcomplication.Theterm

“UTIatriskof complication”ispreferredtotheformerterm

“complicatedUTI”becauseitreferstopatientspresentingwith atleastoneriskfactor,whichmayleadtoamoresevereoramore difficult-to-treatinfection,butthecomplicationdoesnotneces- sarilydevelop.Risk factorsfor complicationincludeorganor functionalabnormalitiesoftheurinarytract(post-voidresidual urine, vesicoureteralreflux, lithiasis,tumor, recenturological procedure, etc.)andsomeunderlyingpatients’ characteristics (male gender,pregnancy, elderly patients with frailtycriteria [seebelow],severechronicrenalfailure[creatinineclearance

<30mL/min],andsevereimmunodeficiency[althoughprecise

“levelsofat-riskimmunodeficiency”cannotbedefined]).“Frail elderlypatients”areindividualsagedover75years(mostpeople of thatagehaveriskfactorsforcomplication)andindividuals agedover65yearspresentingwithatleastthreeFried’sfrailty criteria[3]:unintentionalweightlosswithinthepastyear,slow walkingpace,poorendurance,weakness/fatigue,reducedphysi- calactivity.Comparedwithpreviousguidelines,theagecriterion hasbeenreintroducedtohelpidentifypatientsatriskofpoorer outcome.Diabetesis,however,nolongerconsideredariskfac- torforcomplication:UTIsareindeedmorefrequentlyobserved indiabeticpatients,butUTIsatriskofcomplicationarenot.

Severity criteria must thenbe investigated inpatients pre- sentingwithUTIandsystemicsignsandsymptoms(otherthan cystitis):

• severityof sepsis: severesepsis (Quick SOFA ≥2), septic shock[4];

• orurologicalprocedurerequired(surgicalor interventional, otherthanurinarycatheterization),witharisktoexacerbate thesepsisduringtheprocedure.

Whenseveritycriteriaareobserved,theriskofUTIcausedby anextended-spectrum␤-lactamaseEnterobacteriaceae(ESBL- E)shouldbeinvestigatedbecauseoftheassociatedsubstantial impactontheempiricalantibiotictreatmentchoice.

Keyrecommendations:terminology

• Colonizationmustbedistinguishedfrominfec- tionwhentheurinecultureispositive.

• UTI:

◦ uncomplicated UTIs must be distinguished fromUTIsatriskofcomplication;

◦ severity criteria must be identiﬁed: severity ofsepsis,butalsoinvasiveurologicalproce- dure;

◦ incaseofconﬁrmedseveritycriteria,riskfac- torsfor ESBL-Einfection must be taken into account.

• Mencanpresentwithprostatitis,butalsowith cystitisorpyelonephritis.

1.3. Diagnostictools 1.3.1. Urineteststrip

Urine test strips only have a predictive value by detect- ing leukocytes(sensitivitythreshold:10⁴ leukocytes/mm³) or nitrites. Highlevelsofnitrites(changingof colorofthereac- tion atthethresholdof10⁵CFU/mL)indicatethe presenceof anEnterobacteriaceae. Theotherbacteriacommonlyinvolved inUTIdonotproducenitrites.

Diagnosticperformancesofurineteststripsvarybypatient’s gender.Themainaddedvalueoftheurineteststripinsymp- tomaticwomenisitshighnegativepredictivevalue(>95%)in

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Fig.1.Terminologyandoverallmanagementstrategy.

theabsenceofsevereimmunodeficiency:anegativeurinetest stripmustleadphysicianstolookforanotherdiagnosis[5].The addedvalueoftheurineteststripinsymptomaticmenisitshigh positivepredictivevalue(>90%):leukocyteornitritedetection ishighlyindicativeofUTI.However,anegativeurineteststrip doesnotruleouttheUTIdiagnosis[6,7].

Theurineteststripistheonlyrecommendedexaminationto confirmanuncomplicatedcystitis.TheotherUTIpresentations donotrequireanyurineteststrip,butaurineculturemustbe performed.

1.3.2. Urineculture

A urine culture is indicated for all clinical suspicions of UTI–exceptforuncomplicatedcystitis–andforthediagnosis ofcolonizationrequiringtreatmentadministration(pregnancy, scheduledurologicalprocedure).Acontrolurinecultureisnot requiredduringthefollow-upperiodofanyUTI(includingAPN andmaleUTI),exceptincasesofunfavorableclinicaloutcome.

Aleukocyturiathreshold≥10⁴/mL,obtainedwiththecon- ventional method of optical microscopy, is used to confirm the UTIdiagnosis [8].Thisthresholdmay varyslightly with automated screening devices. One must therefore refer to the reference values indicated on the biological examination report.Thesignificancethresholdforbacteriuriadependsonthe causativebacterialspeciesandonthepatient’sgender(Table2).

Thesethresholds are indicated for referenceonly: in case of clinical symptoms indicative of UTI and bacteriuria or leukocyturialevelslowerthanthethreshold,clinicalsymptoms

Table2

Bacteriuriathreshold.

Bacterialspecies Significantthreshold(UFC/mL) Male Female

E.coli,S.saprophyticus

EnterobacteriaceaeotherthanE.coli, ≥10³ ≥10³ Enterococcus,C.urealyticum,P.aeruginosa,

S.aureus

≥10³ ≥10⁴

takeprecedenceoverthebacteriuria/leukocyturialevels[9].In women,thesignificancethresholdsarenowsimilarforcystitis andAPN.

1.4. Generalprinciplesofantibiotictreatmentand epidemiologyoftheresistanceamongEscherichiacoli strains

Threecriteriamustbetakenintoconsiderationwhenchoos- ingtheantibiotictreatment:

• efficacy,i.e.thecausativeagentmustbesusceptibletothepre- scribedantibioticandthemoleculemustadequatelydiffuse intheinfectedsite;

• tolerability, which must bein line withthe natural history of the treated pathology (a good prognosis for uncomplicated cystitis – which can be cured with a simple

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Keyrecommendations:diagnostic tools

• Urineteststrip:

◦ different performancesinwomen(highneg- ative predictive value) versus men (high positivepredictivevalue).

• Urineculture:

◦ mandatory before antibiotictreatment prescription for all UTIs but uncomplicated cystitis;

◦ unnecessaryas controlurineculture incase offavorableoutcome;

◦ theleukocyturiathresholdmayvarydepend- ing on the method used: one must look at the reference values indicated on the result report;

◦ simpliﬁed bacteriuria thresholds (no more distinction between cystitis and APN in women).

Table3

Prevalenceofantibioticresistancein Francein2016amongE.colistrains responsibleforadultcommunity-acquiredurinarytractinfections.

<5% Fosfomycin-trometamol Generalpopulation Nitrofurantoin Generalpopulation Aminoglycosides Generalpopulation

≈5% 3GCandaztreonam Generalpopulation

<10% Ciprofloxacin,levofloxacin Uncomplicatedandnon-recurrent UTI,intheabsenceof

fluoroquinoloneadministrationin theprevious6months

Pivmecillinam Uncomplicatedcystitis 10to20% Amoxicillin-clavulanicacid Generalpopulation,accordingto

appropriateconcentrationsfor cystitis

Pivmecillinam Cystitisatriskofcomplication Ciprofloxacin,levofloxacin UTIatriskofcomplication TMPandSMX-TMP Uncomplicatedcystitis

>20% Amoxicillin Generalpopulation

Amoxicillin-clavulanicacid Generalpopulation,accordingto appropriateconcentrationsfor APNandmaleUTI TMPandSMX-TMP UTIatriskofcomplication

hyperdiuresis–meansthatadverseeventsareunacceptable, eventhoughuncommon);

• theecologicalimpactonthegutmicrobiotamustbeaslim- itedaspossible.Thecurrentlyusedhierarchyisasfollows:

verysmallimpactforfosfomycin,nitrofurantoin,andpivme- cillinam; high impact for third-generation cephalosporins (3GCs),fluoroquinolones,andtoalesserextentamoxicillin- clavulanic acid and co-trimoxazole; carbapenem sparing strategiesaremandatory.

Resistanceratesaredeterminedbasedondatacollectedfrom varioussurveillancenetworks, withafocuson E.coli strains (mostprevalentspeciesunderclosemonitoring)(Table3)[10].

Resistance levels significantly vary by patients’ characteristics. Physicians must thereforealways refer to the resistance levelofthepatientgroupconcerned.Besides,resistancelevels dependon“breakpoints”(cut-offvaluesdistinguishingsuscep- tiblestrainsfromresistantstrainswhenonlyonebreakpointis available,orsusceptiblestrainsfromstrainswithanintermediate orresistantpatternwhentwobreakpointsareavailable).

Treatmentmaysometimesbedelayeduntilantimicrobialsus- ceptibilitytestresultsareavailable.Theantimicrobialagentwith thenarrowestspectrumcanthusbeprescribedrightaway.Most often, anempiricalantibiotic treatmentisrequired.Treatment must thereforecovermany potentialcausative agentsaccord- ingtoanantibioticresistanceriskleveladaptedtotheclinical criteria:

• ≤20%riskforuncomplicatedcystitis(approximately50%of spontaneouscuresandverylowriskofprogressiontoAPN) [11,12];

• ≤10% risk for APN,male UTI,cystitisinpregnancy,and othercystitispresentationsatriskofcomplication.

Severalpointsshouldbehighlighted:

• since2014,theAntibiogramCommitteeoftheFrenchSoci- etyforMicrobiology/EuropeanCommitteeonAntimicrobial SusceptibilityTesting(CA-SFM/EUCAST)recommendtwo resultsforamoxicillin-clavulanicacid:oneforcystitis(witha breakpointfourtimeshigher)andthesecondonefortheother infections.Asinglestraincanthusbeidentifiedassuscepti- bleforcystitisandresistantforAPN.Usingthebreakpoints forcystitis,resistancetoamoxicillin-clavulanicacidishere around10%whileitisbetween30and40%whenusingthe breakpointsappliedforothersituations[13];

• theefficacyofpivmecillinamwasunderestimatedinformer studies:withthe currentmethod,the susceptibilitylevel is highfor uncomplicated cystitis (>90%) and is compatible withanempiricaluse[14];

• resistanceto fluoroquinolones has become agrowing con- cernworldwide.Itwidelyvariesbypatient’scharacteristics withawell-documentedexcessriskofresistanceinsubjects exposedtothisantibioticclasswithintheprevioussixmonths (irrespectiveoftheindication)[10,15–18];

• resistanceto3GCsrapidlyincreased,reaching5%worldwide, withhereagainsubstantialvariationsbypatient’scharacteristics. ESBLproduction is the mainresistance mechanism [10].AntibioticsstillactiveagainstESBL-producingE.coli strains are fosfomycin-trometamol (>98%), nitrofurantoin (>90%),pivmecillinam(70–90%),aminoglycosides(witha majorbenefitforamikacinover gentamicin:90% suscepti- bilityversus65–70%),cefoxitin(90%),temocillin(60–90%, seebelow),andpiperacillin-tazobactam(>80%). ESBL-Es are still highly susceptible to carbapenems (>99% among E.colistrains).However,alternativesshouldbepreferredas oftenaspossibletopreservethisantibioticclass;

• temocillinisaderivativeofcarboxypenicillinsandisresistant tothe hydrolysis of many ß-lactamases. It has been available in France inthe UTI indication since 2015. The use

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however,higherforESBL-E(40%)[22,23].Consideringcur- rentknowledge,temocillinmustonlybeusedfordocumented infectionscausedbyasusceptiblestrain;

• trimethoprim(TMP)isnowavailableinFrance.Thecurrent susceptibilityratesamongE.colistrainsarealmostsimilar to those of the trimethoprim-sulfamethoxazole combination(SMX-TMP,commonlycalledco-trimoxazole)because TMP-resistant but sulfonamide-susceptible strains are rare [24]. The susceptibility difference observed between both moleculesrangesbetween2%and3%.TheTMP-URsurvey conducted in2016bythe French NationalObservatory for EpidemiologyofBacterialResistancetoAntibiotics(French acronymONERBA) reportedthat 2.6%of co-trimoxazole- susceptiblestrainswereresistanttoTMP[25].TwoFrench studiesreportedaresistancerate<20%amongE.colistrains responsibleforuncomplicatedcystitis,ascollectedbyfamily physicians:12%accordingtoaNormandysurveyconducted in2011–2012[26]and17.5%accordingtoastudyperformed in2014inthewholecountry[27].

Datacollectedfromthe ONERBAnetworksbetween2013 and2016revealsa20%to22%resistanceratetoco-trimoxazole (onemustbearinmindthatnon-recurrentuncomplicatedcystitis doesnotusuallyrequireanyurineculture)[10].

Additional data is thus required to precisely describe the prevalenceofTMPresistanceinuncomplicatedcystitisascom- paredwiththeagreedthresholdof20%.

Keyrecommendations:epidemiology

• Variableresistanceratesdependingonthesub- groupsofpatients.

• Alarmingincreasein E.coli resistance toﬂuo- roquinolonesandtoalesserextentto3GCs.

• EmergenceofESBL-E,reachingsigniﬁcantrates (≈5%)incommunitysettings.

• Uncertainties relating to the resistance rate of trimethoprimprevent any use as an empirical treatment.

• No increase in resistance to fosfomycin- trometamol.

• Low level of resistance (<10%) to pivmecillinam,thusreinforcingitsuseinuncomplicated cystitis.

• asingledoseoffosfomycin-trometamolforthefirst-linetreatment (I-A) because of its numerous advantages (very low acquiredresistancelevel,goodratesforclinicalandmicrobi- ologicaleradication, goodtolerability, singledoseresulting inbetterpatientcompliance,lowimpactonthemicrobiota) [28–31];

• pivmecillinamfor5daysforthesecond-linetreatment(I-A) (sameadvantagesexceptfortreatmentduration)[32–34].

Thereisnooptimalchoiceforthethird-lineempiricaltreat- ment:

• fluoroquinolones are not recommended(healthcare professionalagreement)inthisindicationbecauseoftheirselection pressure,andalsobecausethisantibioticclassshouldbesaved formoresevereinfections[35];

• nitrofurantoinisnot recommended(healthcare professional agreement)inthisindicationinFranceforregulatoryreasons, becauseofitsveryrarebutsevereriskoftoxicity[36];

• theresistanceratestoco-trimoxazole(SMX-TMP)andTMP arecloseto20%[10].

A urine culture is therefore required when neither fosfomycin-trometamol nor pivmecillinam are indicated (extremelyrare)tocontributetothedocumentedantibiotictreat- mentstrategy.Thesamemodalitiesastheonesfordocumented acutecystitisatriskofcomplicationshouldbeimplemented(see below)(healthcareprofessionalagreement).

Reassessmentisnotmandatory,butpatientsmustbeadvised toconsulttheirfamilyphysicianintheabsenceofclinicalcure (functionalsignsandsymptomsusuallydisappearwithin2or 3 days).Aurinecultureisindicatedincaseof treatmentfail- ure(definedasthepersistenceofsignsandsymptomswithout anyimprovementafter3days).Criteriafortreatmentchoiceare thoseusedforcystitisatriskofcomplication(seebelow).

Treatmentdurationshouldnotbechangedincaseoftreatment failure,newtreatmentline,or ESBL-Ecystitisifthestrain is fullysusceptibletotheprescribedagent.

1.5.2. Cystitisatriskofcomplication

Aurineculture mustalways beperformed (II-B).The eti- ology of the infection will be investigated on acase-by-case basisdependingontheriskfactorforcomplication.Whenacute urinaryretentionissuspected,asimplifiedexaminationofpost- voidresidualurineusingultrasound(e.g.,Bladder-scan^TM)must beperformed.Ifthisexaminationcannotbeperformed,aurinary tract ultrasonography must be performed. This type of investigationisparticularlyusefulinelderlypatients.

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Fig.2.Uncomplicatedcystitis.

Keyrecommendations

• Fosfomycin-trometamol for the ﬁrst-line treatment, pivmecillinam for the second-line treatment.

• Fluoroquinolones and ceﬁxime are no longer used for the empirical treatmentof uncomplicatedcystitis.

• Strategy based on the urine culture results in case of contraindication to both fosfomycin- trometamolandpivmecillinam(althoughrare) orincaseoftreatmentfailure.

Thekeyrecommendationistodelaytheantibiotictreatment, wheneverpossible,todirectlyprescribeatreatmenttailoredto theantimicrobialsusceptibilitytestresults(Fig.3)(healthcare professionalagreement).

Newrecommendations:cystitisatrisk ofcomplicationcan nowbetreatedwith3dosesoffosfomycin-trometamol;fluoro- quinolonesarenotrecommendedinthisindication.

Theriskofantibioticresistanceismuchhigherinthispopula- tionofpatientsthaninpatientspresentingwithuncomplicated cystitis,because underlying urinarytractdisorders or comor- bidities mayrequire repeated coursesof antibiotic treatment.

Not prescribing abroad-spectrumantibiotic, evenfor a short period of time, helpspreserve the bacterial ecology of these femalepatients,andfacilitatestreatmentofsubsequentepisodes bypreventingtheselectionofmultidrug-resistantbacteria.On thebasisoftheantimicrobialsusceptibilitytestresults,theagent withthebestprovenefficacyandthelowestselectionpressure onthemicrobiota(IV-C)shouldbechosen:i.e.,amoxicillin(7 days)forthefirst-linetreatment,pivmecillinam(7days)forthe second-linetreatment,nitrofurantoin(7days)forthethird-line treatment,fosfomycin-trometamolforthefourth-linetreatment (3doseseachadministered48hapart),andTMPforthefifth-line treatment(5days).

Nitrofurantoin and fosfomycin-trometamol may be used when treatment initiation cannot be delayed (highly symp- tomaticfemalepatient,etc.)–thismustremainrarethough:

• nitrofurantoin (III-B) (except in patients presenting with aknown renal failure [creatinine clearance <40mL/min]), because of the associated low risk of resistance andwell- establishedefficacy,includingagainstESBL-E[37];

• fosfomycin-trometamol (III-B), because it is still active againstmorethan95%ofE.colistrainsisolatedfrompatients presentingwithcystitisatriskofcomplication,withoutany realdifferencewiththeprevalenceofresistanceinuncompli- catedcystitis[38–40],andbecauseofitsexcellenttolerability profile.However,itsefficacyisnotwellestablishedinpatients presentingwithcystitisatriskofcomplication,andthethree- doseregimenisstilladministeredoff-label.

Cefixime andfluoroquinolones (suggestedfor the second- lineempiricaltreatmentuntil2015)arenolongerrecommended (healthcareprofessionalagreement)becauseoftheirsubstantial ecological impact andof amuchhigher resistancelevel than nitrofurantoinandfosfomycin-trometamolinthesepatients.

Dataisstilllimitedtorecommendtheuseofpivmecillinam fortheempiricaltreatmentofthisinfection(healthcareprofessionalagreement). Reassessmentismandatoryas soonas the antimicrobial susceptibility test results are available, and the antibiotic is chosen accordingtothe above recommendations fordelayedtreatment.

Thefollow-upisthensimilartothatofuncomplicatedcystitis:

noconsultationandnoroutineurineculturerequired.

1.5.3. Recurrentcystitis

Definedasatleast4episodesover12months[41],twopre- sentationsofrecurrentcystitisareusuallyobserved:

• thoseassociatedwithoneormoreriskfactorsforcomplica- tion(mainlyneurogenicbladder)[42];

• thoseobservedintheabsenceof underlyingurologicaldis- orderor otherrisk factorsforcomplication(most common presentation).

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Fig.3.Cystitisatriskofcomplication.

Key recommendations: cystitis at risk of complication

• Treatment should be delayed to directly pre- scribeanappropriateagentonthebasisofthe antimicrobialsusceptibilitytestresults;

• For the rare cases requiring an empirical treatment: ﬁrst-line nitrofurantoin (except for patients presenting with a known renal fail- urewithcreatinineclearance <40mL/min)and second-linefosfomycin-trometamol;

• Fluoroquinolones and ceﬁxime should no longer be used for the empirical treatment of cystitisatriskofcomplication.

A urine culture is indicated for initial episodes of recurrence (IV-C). A clinical examination must be performed in women of childbearing potential (mainly pelvicand urethral examinations),andurinarytractdisordersmustbeinvestigated (please refer to the French Urological Association website:

http://www.urofrance.org/congres-et-formations/formation- initiale/referentiel-du-college/troubles-de-la-miction.html).

Results of these examinations must be confirmed by the anamnesisandifpossiblebyamicturitiontimechart(available from the French Urological Association website). Other investigationsarenotrecommended(II-B)[42].

Acheck-upmust bediscussedfor othersituations,withat the veryleast a urinarytractultrasound andan evaluationof post-voidresidualurine.Dependingonthecontext,thefollow- ingexaminationsmustalsobeperformed:uroflowmetrywithor withouturodynamictesting,urinarytractCTscanorultrasound, cystoscopy,retrogradecystography,gynecologicalexamination (IV-C).

Treatmentofrecurrentcystitisinpatientspresentingwithrisk factorsforcomplicationisbasedonamultidisciplinarydecision includinganinfectiousdiseasespecialist,aurologist,agynecol- ogist,andaradiologist.Thesecase-by-casestrategiescannotfall understandardizedrecommendations.

Treatmentofrecurrentcystitisinpatientspresentingwithout anyriskfactorsforcomplicationisasfollows(Fig.4):

• thecurativetreatmentofacuteepisodes issimilartothatof uncomplicated cystitis.Nitrofurantoin is notrecommended in this indication (risk of severe toxicity increased by the re-introductionofthesamedrug).Followingtherapeuticedu- cation,somefemalepatientsmayreceiveaself-administered treatment: the urine test strip is performed by the patient and, when positive, is followedbyapreviously prescribed antibiotictreatment.Requiringtworeassessmentsayear,this strategycontributestoreducingthedurationofdiscomfortand theantibioticexposureascomparedwithaprolongedantibi- oticprophylaxisstrategy.Someself-medicationpracticescan thusbebetterregulated(II-B)[43,44];

• variousprophylacticstrategieswithoutanyantibioticsmaybe suggested,althoughtheirefficacyhasnotalwaysbeenwell- established [45]:(a)sufficientwaterintake(1.5L/24hr),no restraintfromurinating,andimprovedbowelmovement(IV- C); (b) cessationof spermicide use(although quiterare in France)(III-C);(c)cranberryconsumptionwith36mg/dayof proanthocyanidin(IV-C);(d)localapplicationofestrogensin menopausalwomenonthebasisofthegynecologist’sadvice (IV-C);

• long-term antibiotic prophylaxis should really be avoided becausewheneffective(lowerfrequencyofcystitis)itisasso- ciated with resistance and toxicity risks of whichpatients should be informed. Such antibiotic prophylaxis does not change the natural history of the disease (very frequent recurrencesupondiscontinuation)(I-A)[46].Nitrofurantoin shouldnolongerbeusedinthisindicationbecauseofsevere

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Fig.4.Recurrentcystitis.

complicationshighlycorrelatedwithtreatmentduration(lung fibrosis,fulminanthepaticfailure)(IV-C).␤-lactamsandflu- oroquinolonesareessentialforthecurativetreatmentofAPN andshouldthereforebespared(healthcareprofessionalagreement). TMP is interesting in this indication (I-A) and is nowavailableinFrance.Otherwise,theadministrationofthe followingagents maybediscussed: co-trimoxazole(SMX- TMP;advantage:well-establishedefficacyinthisindication;

disadvantages: impact on the microbiota, rare but severe allergicreactions),andfosfomycin-trometamol(advantage:

smallimpactonthemicrobiota;disadvantages:efficacynot aswellestablished,essentialmoleculeforthecurativetreat- ment of cystitis) (I-A) [47,48]. Antibiotic prophylaxis is usually only discussed in female patients presenting with at least one episode per month, andwhen otherstrategies havefailed.Antibioticsarerecommendedforpost-coitalcys- titis,2hbeforeor2haftertheintercoursewithoutexceeding thefrequencyoftheusualcontinuousprophylaxis.Theopti- maldosingregimenisyettobedetermined[46].SMX-TMP dosing regimen of 200–40mg/day or 400–80mg/day and 100mg/dayforTMPwerevalidatedinthe1980s.Atthattime, the prevalence of Enterobacteriaceae resistance was much lowerforbothagents.AsTMPisonlydispensedinFrance as 300 mgtablets,adailydosingregimenof150 mg(half atablet)issuggestedandthe400–80mg/daydosageshould keeponbeingusedforSMX-TMP(forcontinuousprophy- laxis,tabletsshouldbetakenatbedtimeinbothofthesecases).

Astudyassessingfosfomycin-trometamolvalidatedtheuse ofa3g-sachetevery7days(IV-C)[49].

Clinicalmonitoringonlyisrequired.Routineurinecultures arenotrecommended,asthetreatmentobjectivesaretocontrol symptomsandnottosterilizeurine.Aurinecultureshouldstill beperformedincaseofclinicalfailure.

Keyrecommendations:recurrentcystitis

• Pelvic clinical examination, urination disorder investigation,andmultidisciplinaryapproachin caseoffrequentepisodes(≥1/month).

• Up to one episode per month: curative treatment,self-initiationbythefemalepatient.

• More than one episode per month: antibiotic prophylaxis only when other strategies have failed (TMP or fosfomycin-trometamol; nitrofurantoin should never be prescribed in this indication).

1.6. Pyelonephritis 1.6.1. Background

TreatmentoffemaleAPNdiffersdependingonthepresence orabsenceofseveritycriteria(Fig.5).MaleAPNandpregnancy presentationsarediscussedinSections6and7.

Aurineteststripisalwaysrecommended(IV-C)andaurine cultureismandatory(II-C).Otherbiologicalandimagingexam- inationsdependontheAPNpresentation.

MostAPNpatientsreceiveanoutpatienttreatment(empiri- caltreatment orfollowingashorthospitalsurveillance)(II-B) [50].Indicationsforhospitalizationareseveritycriteria,hyper- algesia, diagnostic uncertainty, vomiting – no oral treatment is thereforepossible–, potentialcomplianceissueor difficult surveillance(isolationofpatients),hospital-useonlyantibiotic treatment(rarecasesofmultipleallergicreactionsormultidrug resistance),decompensationofacomorbidity.

Assoonastheurinecultureisperformed,anempiricalantibi- otictreatmentisinitiated.Treatmentshouldthenbereassessed on the basis of the antimicrobial susceptibility test results (II-B)[51].Theinitialantibioticchoiceandtheoveralltreatment durationdependontheAPNpresentation.Thetreatmentswitch

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Fig.5.Overallmanagementofpyelonephritis.

strategyisthesameforallclinicalpresentations.Theagentwith thenarrowestspectrumbasedontheantimicrobialsusceptibil- itytestresultsshouldbeprescribedasanoraltreatment,except forspecificcases(uncontrolledinfection,especiallywhenresis- tancetotheempiricaltreatmentisobserved;nooraltreatment possible).

Anyobstacleontheurinarytractshouldberemovedtocontrol theinfection:acuteurinaryretentionshouldbeexcludedusing portable ultrasound devices at bedside (especially in elderly subjects) and the bladder should be catheterized if required;

ureteropelvicjunctionobstructionrequiringinstrumentalorsur- gicaldrainage shouldbeinvestigated (healthcareprofessional agreement).

1.6.2. Pyelonephritiswithoutseveritycriteria

Bloodculturesarenotrequired,exceptincaseofdiagnostic uncertainty.Complete bloodcount, CRP,andcreatinine level areonlyrecommendedforAPNatriskofcomplication(III-C) [52,53].

The imaging strategy is as follows: no imaging examination is required for a first episode of non-hyperalgesic APN witharapidly favorableoutcome [54] (III-B);ultrasound for the other presentations of uncomplicated APN; urinary tract CT scan or ultrasound (in case of contraindication or non- availabilityoftheurinarytractCTscan)withinthefirst24hfor APNatriskofcomplication,hyperalgesicpresentations,andin caseofanunfavorableoutcome72hafterantibiotictreatment initiation.

1.6.2.1. Uncomplicated APN. The empirical antibiotic treatment for uncomplicated APN (Fig. 6) is firstly based on a fluoroquinolone (ciprofloxacin,levofloxacin),unless afluoro- quinolonehasalreadybeenprescribedintheprevious6months –irrespectiveofthereason(I-A)[55,56].Fluoroquinoloneshave numerous advantages: excellent bioavailability (even though lowerforlomefloxacinandnorfloxacin;bothoftheseagentsare thereforenotconsideredinthisindication),oraladministration, short treatment duration(7 days),lower impactonthe selec- tionofESBL-Ethan3GCs.Limitationsoffluoroquinoloneuse are theirheterogeneous resistancerate accordingtothestudy population and local ecology, which is now above 10% for ofloxacin(nolongerrecommendedasanempiricaltreatment) butbelow10%forciprofloxacinandlevofloxacinforuncompli- catedAPNintheabsenceofexposuretofluoroquinoloneswithin theprevious6months[10,18,57].Whenfluoroquinoloneshave beenadministeredintheprevious6 months,thealternative is aparenteral3GC(cefotaximeorceftriaxone-onlythelatteris availableincommunitysettings)[58].Whenfluoroquinolones and 3GCs are contraindicated, the prescription of an aminoglycoside(amikacin,gentamicin,ortobramycin)oraztreonam (hospitaluseonly)shouldbeconsidered[59].Oral3GCsarenot recommendedasafirst-linetreatment(healthcareprofessional agreement)[60,61].

The recommended treatment duration for uncomplicated APN is 7 days with fluoroquinolones and injectable beta- lactams, and 10 days with the other antibiotics (B-II). Few studies validated a 5-day treatment duration with fluoroquinolones for uncomplicated APN, but these findings must

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Fig.6.Empiricaltreatmentofpyelonephritis(APN).

be confirmed[62,63].Treatmentduration maybe reduced to 5 daysonthe rareoccasions whenanaminoglycosideis pre- scribedforthewholetreatmentduration(healthcareprofessional agreement)[64].

1.6.2.2. APN without severity criteria, but at risk of complications. Thesameempiricalantibiotictreatmentstrategy shouldbeimplementedinthisindication,andinjectable3GCs shouldbepreferred(higherantibiotic resistanceinthispopu- lationofpatients,especiallywithfluoroquinolones)(healthcare professionalagreement)[10,18].

TreatmentdurationforAPNatriskofcomplicationis10to 14days(exceptforpregnantwomen)(II-B):10daysareenough whenthecausativeagentissusceptibletotheempiricalantibi- otictreatmentandwhenarapidlyfavorableoutcomeisobserved (healthcare professionalagreement). However,alonger treat- mentdurationissometimesrequiredandmustbediscussedon acase-by-casebasis(seeSevereAPNbelow)(IV-C).

TreatmentdurationformaleUTIisdiscussedseparately(sec- tion7).

1.6.2.3. Antibiotictreatmentswitch. Onthebasisoftheantimi- crobialsusceptibilitytestresults(Fig.7),amoxicillinshouldfirst beprescribedforAPNcausedbyasusceptiblestrain.Otherwise, amoxicillin-clavulanic acid, fluoroquinolones (ciprofloxacin, levofloxacin,orofloxacin),cefixime,orco-trimoxazole(SMX- TMP)shouldbeconsidered.

An ESBL-E-specific strategy has been outlined (Table 4) tosparecarbapenemsasmuchaspossible,evenmoresowith emergingcarbapenemase-producingEnterobacteriaceae(CPE).

ThisESBL-E-specificstrategyshouldbeadaptedonacase-by- casebasisaccordingtoco-resistanceandanticipatedtolerability factors.The5-daymonotherapywithanaminoglycosidecanfor instanceleadtorenalorcochlear-vestibulartoxicity,whichmust

betakenintoconsiderationwhenassessingthebenefit-riskratio ([65]).

Clinical monitoring only is required as the control urine cultureisonlyindicatedincaseofclinicalfailureorsymptomatic recurrence(IV-C).

1.6.3. Severepyelonephritis

An even safer strategy is required,in terms of additional examinations andantibiotic choice,whenseveritycriteria are observed(QuickSOFAscore≥2[4],severesepsis,septicshock, butalsourinedrainagebyanyothermeansthanurinarycatheter- ization).

Bloodcultures,completebloodcount,CRP,urea,andcrea- tininelevelaremandatoryinthisindication(IV-C).Aurinary tractCTscan(oranultrasoundincaseofcontraindication)is indicated,mostoftenasanemergencymeasureorwithin24h (IV-C).

Fluoroquinolonesshouldnotbeusedfortheempiricalantibi- otictreatment(Fig.6)astheresistancerateisextremelyhighin thesepresentations,forwhichtheriskofinitialfailuremustbe verylow.

A combination treatment with a ␤-lactam and an aminoglycoside is recommended for all severe APN presentations (rapidbactericidalactivity,synergisticeffectwiththeassociated

␤-lactam,highintrarenalconcentration) (II-B) [66–68].Only amikacinisrecommendedinthisindicationtobettercoverthe possibilityofanESBL-E(theriskofcross-resistanceissubstan- tiallylowerwithamikacinthanwithgentamicinortobramycin).

The␤-lactamchoicedependsontheevaluationoftheriskof ESBL-Einfectionandonseveritycriteria:

• femalepatientspresentingwithfactorsindicativeofthesever- ityof sepsis(qSOFAscore≥2,formerly known assevere sepsis) without any septic shock, or requiring urological

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Fig.7.Treatmentswitchforpyelonephritis(APN).

Table4

DocumentedantibiotictreatmentofESBL-Epyelonephritisinpregnancy.

Firstchoice Ciprofloxacinorlevofloxacin co-trimoxazole(SMX-TMP) Secondchoice Amoxicillin-clavulanicacid Thirdchoice Cephamycin(cefoxitin)

Orpiperacillin-tazobactam Ortemocillin

Fourthchoice Aminoglycoside(amikacin,gentamicin, tobramycin)

5thline Carbapenem(imipenemormeropenem,

ertapenemasatreatmentswitch)

Treatmentchoicedependsonthepatient’scharacteristicsandontolerabilityand administrationmodalitiesdata.

procedure,andwithoutany historyofUTIor ESBL-Ecol- onization in the previous 6months, must receive a 3GC (cefotaxime or ceftriaxone)associated withamikacin.This aminoglycosidehasindeedahighprobabilityofbeingactive againstapotentialESBL-Enotdetectedduringtheanamnesis whilethe3GCismostoftennoteffective(IV-C).Theempir- icalantibiotic treatment prescribed must take into account patients presenting with a historyof UTI or ESBL-E uri- narytractcolonizationintheprevious6months(I-A).Prior microbiologicaldatamustalwaysbeconsidered,ifpossible (forinstance,useofpiperacillin-tazobactamforahistoryof ESBL-Edocumentedassusceptibletothatantibiotic)(healthcareprofessionalagreement).Otherwise,theempiricalchoice

mustbeacarbapenem(imipenemormeropenem)associated withamikacin.Indeed,carbapenemsremainthegoldstandard forthemostsevereESBL-Einfections[69];

• risk factors for ESBL taken into consideration are wider for patients presenting with septic shock. The empirical antibiotic treatment protocol must be switched to carbapenem+amikacin in the following situations: ESBL-E UTIor urinarytractcolonizationinthe previous6months, amoxicillin-clavulanic acid/2GCs/3GCs/or fluoroquinolone prescription inthe previous 6 months,travel toan ESBL- Eendemicarea,orhospitalizationinalong-termcarefacility [70,71].Consideringtheextremeseverityofthesepticshock, carbapenemsarerecommendedinthisindication(healthcare professionalagreement).

Forpatientspresentingwithanallergyto3GCsorcarbapen- ems,thealternativeisaztreonam.

Thesetreatmentprotocolsmustthenbereassessed48hafter initiation,andphysiciansmuststrivetoreducethespectrumof activityfollowingtheaboveguidelinesforAPNwithoutseverity criteria.

Theoveralltreatmentdurationis10days,butlongertreat- ment durations may sometimes be required (mainly when a renal abscess is observed)and must be discussed on acase- by-casebasis(IV-C).Anyobstacleontheurinarytractmustbe urgentlyremoved,andaclosemonitoringmustbeimplemented.

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Followingurinarytractobstructiondrainage,atemporarywors- eningofsepsismaybeobserved.

Follow-upismainlybasedon clinicalmonitoring,andthe urinecultureisnotmandatory.Urineculturescansometimesbe indicatedthough,especiallyforpatientspresentingwithlithiasis andAPNtoruleoutachronicinfection.

Keyrecommendations:pyelonephritis

• Different strategies for uncomplicated and at- risk presentations, which also depend on the presenceorabsenceofseveritycriteria.

• Fluoroquinolones are still recommended for the empirical treatment (ciproﬂoxacin or lev- oﬂoxacin)ofuncomplicatedAPNwithoutsever- ity criteria when quinolones have not been administeredintheprevioussixmonths.

• TheriskofESBL-Einfectionmustbetakeninto accountwhenchoosingtheempiricaltreatment forsevereAPN.

• Speciﬁc guidelines for ESBL-E-documented APN.

1.7. Urinarytractinfectionsinpregnancy 1.7.1. Urinarytractcolonizationinpregnancy

Thediagnosisreliesonapositiveurineculture,withaculture yieldingasinglebacteriumatatiter≥10⁵CFU/mL(toclearly make thedistinction betweencolonizationandcontamination due to a poor-quality sample in these asymptomatic female patients,the thresholdis voluntarilyhigherthantheoneused forUTI).Ideally,twopositiveurineculturesyieldingthesame strain andperformed oneweekapart minimum, are required toestablishthediagnosis.However,for practicalreasonsit is admittedthatonlyoneurinecultureissufficient.

Amonthlyscreeningforcolonizationisrecommendedinall pregnantwomenasofthefourthmonthofpregnancybecause ofa20–40%riskofpyelonephritisincaseofurinarytractcol- onizationinthispopulation[72].Screeningisbasedonaurine teststrip(II-B),exceptforpregnantwomenathighriskofUTI (knownurologicaldisorder,diabetes,historyofrecurrentcys- titis)forwhomaurineculturemustimmediatelybeperformed (II-B)[73].

Treatmentismandatory(I-A)asitsignificantlyreducesthe riskofsymptomaticUTIanditsimpactonthemotherandfetus.

The treatment must initially be tailored to the antimicrobial susceptibilitytestresults(Fig.8).Moleculeswiththenarrowest spectrumpossible,thesmallestimpactonthegutmicrobiota, andthebestmaternalandfetaltolerabilityshouldbepreferred, i.e.,amoxicillin forthe first-linetreatment,pivmecillinamfor thesecond-linetreatment (IV-C)[74],fosfomycin-trometamol forthethird-linetreatment(II-B)[75],TMPforthefourth-line treatment, and the following agents for the fifth-line treatment (order based on their impact on the gut microbiota):

Fig.8. Treatmentofurinarytractcolonizationinpregnancy.

nitrofurantoin, co-trimoxazole (SMX-TMP), amoxicillin- clavulanic acid, and cefixime. TMP and co-trimoxazole (SMX-TMP) must beavoidedduring the firsttwo months of pregnancy.

The recommendedtreatment durationis a singledose for fosfomycin-trometamoland7daysfortheothertreatmentreg- imens(II-B)[76].Aurinecultureisrecommended8to10days aftertreatmentdiscontinuation.Itmustthenbeperformedona monthlybasisuntilthepatientgivesbirth.

Urinary tract colonization with group B Streptococcus requiresperpartumneonatalinfectionprevention–evenwith

“non-significant” titer (the urinary tract colonization usually presentswithvaginalcolonizationatriskofpersistenceorrecur- rence) [77]. Patients presenting with significant titers (≥10⁵ CFU/mL)mustbetreatedforpregnancy-relatedcolonizationas mentionedabove(IV-C)[78].

Key recommendations: urinary tract infec- tioninpregnancy

• Mandatory screening with a urine test strip (withaurinecultureforthemostat-riskgroups) fromthe4thmonthofpregnancy.

• Treatment of colonization ≥10⁵CFU/mL, directly adapted to the urine culture results and antimicrobial susceptibility and favoring amoxicillin, pivmecillinam, and fosfomycin- trometamol.

• ColonizationorUTI:controlurineculture8to10 days after treatment discontinuationand then onamonthlybasisformonitoringpurposes.

• Positive culture for group B Streptococcus:

treatmentofcolonizationiftiter≥10⁵CFU/mL, andperpartumprophylaxisirrespectiveofthe titer(becausethisisindicativeofavaginalcol- onization).

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Fig.9.Treatmentofcystitisinpregnancy.

1.7.2. Cystitisinpregnancy

Aurinecultureisalwaysindicated,andthesameinterpre- tationthresholdsastheonesrequiredforUTIinnon-pregnant womenapply.

An empirical antibiotic treatment mustbe initiated before receiving the results of the antimicrobial susceptibility test because of the progression risk to APN. Choice criteria are alow risk of resistance (10% threshold inthisindication), a provenefficacy,anexcellentmaternalandfetaltolerabilitypro- fileincludingintermsofselectionpressureonthegutmicrobiota (incaseofneonatalinfection,themainriskfactorforESBL-E isthemother’sexposureduringpregnancytoanantibioticwith astrongimpactonthegutmicrobiota).

Theonlyrecommendedfirst-linetreatment(Fig.9)isasingle dose of fosfomycin-trometamol (II-B) as recent studies con- firmedthatsingledoseregimensareeffectiveinthetreatment ofcystitisinpregnancy.Themoleculeisalsoassociatedwitha lowprevalenceofresistancetoantibiotics,anexcellentmaternal andfetaltolerability,andaminorimpactonthegutmicrobiota [79].Theuseofpivmecillinamissuggestedforthesecond-line treatment(IV-C)[80].Althoughveryrare,thethird-linetreat- mentmustrelyonnitrofurantoin,cefixime,orciprofloxacin(the onlyfluoroquinoloneindicatedduringpregnancybecauseofa well-establishedandreassuringpharmacovigilance).

The antibiotic treatment must be reassessed as soon as possible basedon the antimicrobial susceptibility testresults and on clinical outcome. Considering the current ecology, a treatmentswitchisunlikelywhenasingledoseoffosfomycin- trometamol is prescribed as the first-line treatment. When a treatmentswitchisrequired,thestrategyusedforcolonization inpregnancy applies: amoxicillin for the first-line treatment, fosfomycin-trometamol or pivmecillinam for the second-line treatment (depending on the prior treatment), TMP for the

The recommended treatment duration is asingle dose for fosfomycin-trometamoland7daysfortheothertreatmentreg- imens(healthcareprofessionalagreement).

Aurinecultureisrecommended8to10daysaftertreatment discontinuation.Itmustthenbeperformedonamonthlybasis untilthepatientgivesbirth.Treatmentmustbeprescribedwhen acolonizationdiagnosisisestablished[healthcareprofessional agreement].

Keyrecommendations:cystitisinpregnancy

• Mandatoryurineculture,followedbyanempir- icalantibiotictreatment.

• Treatment of cystitis in pregnancy is similar to that of uncomplicated cystitis: fosfomycin- trometamol for the ﬁrst-line treatment and pivmecillinamforthesecond-linetreatment.

1.7.3. Pyelonephritisinpregnancy

The strategyis very similartothe onefor APNatrisk of complicationinthegeneralpopulation,withjustafewspeci- ficities.

Aurinecultureismandatory.Bloodculturesarerequiredfor severepresentationsordiagnosticuncertainties(feverinpatients presentingwithurinarytractcolonizationforinstance).Auri- narytractultrasoundisrequiredandmustbeurgentlyperformed whenconfrontedwithsevereorhyperalgesic presentations.A gynecologyconsultationismandatory,irrespectiveofthepreg- nancystage.

Initial hospitalization is quite common. Outpatient treat- mentmaybeprescribeduponinitialexaminationatthehospital whenthe followingcriteriaaremet:goodclinicaltolerability, non-hyperalgesicpresentation,novomiting,normalobstetrical examination,possibilityofhomesurveillancebycloserelatives, absenceofimmunodeficiency,norecurrentUTI,andnounder- lyingurologicaldisorder.

The empirical antibiotic treatment for APN in pregnancy without severity criteria relies on a parenteral 3GC [81].

Ciprofloxacin may be used as an alternative in patients presentingwith␤-lactamallergy,withatreatmentswitchaiming at avoiding co-trimoxazole (SMX-TMP) during the first two monthsofpregnancy(IV-C).TheantibiotictreatmentforAPNin pregnancywithoutseveritycriteriaorforESBL-Edocumented APN is similar to that prescribed to the general population (healthcareprofessionalagreement).

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Clinical monitoring of the mother andfetusis mandatory, especiallyat 48–72h of treatment. Aurineculture isrecom- mended 8 to10 daysafter treatment discontinuation. It must thenbe performed ona monthlybasisuntil the patient gives birth.

Keyrecommendations:acutepyelonephritis inpregnancy

• Mandatory obstetrical examination and com- moninitialhospitalization.

• SimilartreatmentastheoneforAPNatriskof complications.

1.8. Maleurinarytractinfections

The term “maleUTI”is now used instead of “prostatitis”

(toorestrictive).Althoughtherapeuticmodalitiesmaybesimi- lar,maleUTIsarehighlyheterogeneousintermsofclinicalsigns and symptoms (from pauci-symptomatic presentations with- outfever[knownas“cystitis-like”]toobviousparenchymatous involvementthat canleadtosepticshock).Presentationswith clearclinicalsignsof prostateinvolvementmayobviouslybe referredtoasprostatitis.Somepatientsmaypresentwithapre- dominanceofAPNsignsandsymptoms,whileothersonlyhave functionalurinarysymptoms withoutanysystemicmanifesta- tion.

Anegativeurineteststripinmalepatients presentingwith urinary functional signs cannot rule out the UTI diagnosis (lownegativepredictivevalue),whileapositiveurineteststrip reinforces the diagnostic suspicion (high positive predictive value)[6,7].Theurineculturecontributestotheinfectiondoc- umentationandtoguidingtreatmentprescription.Aurinetest stripisthereforerecommendedinmalepatients,andtheurine cultureismandatory.Abloodcultureisindicatedwhenfeveris observed[82].Prostate-specificantigen(PSA)testingisnotrec- ommendedduringtheacutephaseoftheinfection.Anegative resultdoesnotruleoutaprostateinfection,andapositiveresult cannothelp distinguishprostatitis,hyperplasia,or underlying cancerduring the firstfew monthsof the infection: 6months maximumafterinfectiononsetarerequiredtoreturntobaseline level[83](IV-C).

Imaging testsrely onsuprapubic urinary tract ultrasound, whichmustbeurgentlyperformed(<24h) incasesof severe sepsisandwhenacuteurinaryretentionorlithiasisaresuspected (healthcare professional agreement).Endorectal ultrasound is not recommendedduringthe acutephase of the infection,as it is extremely painful. It should be discussed at the initial phasewhen aprostate abscessissuspected(acutepain,unfa- vorableoutcome)andasanalternativetotheMRI.Endorectal ultrasoundshouldlaterbeconsideredwheninvestigatingcon- tributingfactorsforUTI(adenoma,cancer,etc.cansometimes bediagnosed).Althoughlesseffectiveforprostateanalysis,an

x-raymaybeindicatedtovisualizetherestoftheurinarytract dependingonwarningsignsandoutcome.

Manypresentationsmaybemanagedwithanoutpatienttreat- mentascriteriaforhospitalizationarethoseofAPN.Agradual therapeutic strategymustbeadoptedconsideringthediversity of clinicalpresentations(Fig.10):the antibiotictreatment for pauci-symptomaticmaleUTImaybediffereduntiltheantimi- crobialsusceptibilitytestresultsareavailable,soastodirectly prescribethe besttreatment;an empiricalantibiotic treatment isindicatedincaseoffeverorpoortolerabilityofurinarytract symptoms,anditmustinitiallybesimilartothatofAPNatrisk ofcomplicationbutwithoutseveritycriteria.Ciprofloxacinand levofloxacincanthusbewidelyused(IV-C).Patientspresenting withacuteurinaryretentionorsevereimmunodeficiencybutno otherconcerningclinicalsymptoms,mustbehospitalizedand thesameempiricalantibiotictreatmentastheoneprescribedfor APNwithoutseveritycriteriabutatriskofcomplication,must be prescribed. Parenteral 3GCsare therefore most frequently favored(healthcareprofessionalagreement).Patientspresenting withseveritycriteriamustbetreatedwitha␤-lactam+amikacin combination.The␤-lactamchoicemusttakeintoconsideration thepresenceofriskfactorsforESBL-Einfection.

Prostatitis cannot be ruled out even when no symptoms indicative ofthisdiagnosis areobserved[84].Inlight ofcur- rent data, the antibiotic treatment switch must always favor molecules with a good prostate diffusion (healthcare professionalagreement).

Fluoroquinolones (ciprofloxacin,levofloxacin,orofloxacin when thestrain has been documented as susceptible) are the reference molecules for the treatment of male UTIs (II-B):

their prostate diffusionis excellent andtheir efficacy against susceptible strains has already been proven. Unlike female UTIs,fluoroquinolonesarepreferredforthetreatmentofdocu- mentedmaleUTIscausedbysusceptiblestrainsevenwhenother moleculeswithanarrowerspectrumare available(becauseof theirexcellentprostatediffusion).

Co-trimoxazole(SMX-TMP)canbeusedasanalternativein thetreatmentofmaleUTIscausedbysusceptiblestrains:good prostatediffusion,butlittleclinicalefficacydataisavailable(III- C).TMPcannolongerbeusedinthisindicationasclinicaldata islacking.

Variousalternativestrategies (Table5)aresuggestedwhen neither fluoroquinolonesnorco-trimoxazole(SMX-TMP)can beused,especiallyforESBL-EUTIs.Thealternativestrategies are basedondiffusiondataandonsmallclinical studies(III- C). Treatmentof enterococcalUTIand UTIcaused byother uncommonmicrobialspeciescannotbestandardizedinlightof theavailablescientificliteraturedata.

Treatmentfailuremaybetriggeredbyanuntreatedunderly- ingurologicaldisorder(IV-C)[85].

Thereiscurrentlynodataavailabletoadjusttreatmentdura- tion onthebasisof theinitial clinicalpresentation.A14-day treatmentdurationisrecommendedforinfectionstreatedwith fluoroquinolones or co-trimoxazole (SMX-TMP), except for the uncommoncasesof abscessthatmayrequireaprolonged treatment (IV-C)[86].Aprolonged21-daytreatment mustbe discussedforpatientspresentingwithuncontrolledunderlying

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Fig.10.Managementofmaleurinarytractinfections.

Table5

Treatmentofdocumentedmaleurinarytractinfections.

Non-ESBL-producing Enterobacteriaceae

ESBL-producing Enterobacteriaceae Firstchoice Ciprofloxacin,

levofloxacin

Ciprofloxacin, levofloxacinorofloxacin Orofloxacin

Secondchoice Co-trimoxazole (TMP-SMX)

Co-trimoxazole (TMP-SMX) Thirdchoice Cefotaximeorceftriaxone Cefoxitin

Or

Piperacillin-tazobactam Or

Temocillin

Fourthchoice Imipenem

Meropenem Ertapenem

(if≥80kg:1gtwicea day)

urologicaldisorderorwhentreatmentrequiresmoleculesother thanfluoroquinolones,co-trimoxazole,orparenteral␤-lactams (healthcareprofessionalagreement).

Urinarydrainagebyurethralcatheterorsuprapubiccatheter must be performed in patients presenting withacute urinary retention (IV-C) [87]. Antibiotic treatment alone is usually enoughincaseofprostateabscesses.Surgicalor instrumental drainagemayberequiredincaseofunfavorableoutcome,and despitetheadministrationofanadequateantibiotictreatment.

In case of favorable outcome, acontrol urine culture performed during treatment or after treatment discontinuation is notrecommendedaspersistentcolonizationwouldnotbetreated (healthcareprofessionalagreement).

MalepatientspresentingwithaninitialepisodeofUTImust haveadetailedanamnesisandclinicalexaminationperformed toscreenfor anatomicaland/orfunctionalabnormality of the urinarytract(e.g.,bladderorprostateabnormality):pollakiuria, urgeurination,reducedurineflow,nycturia,dysuria,orabnor- mality at digital rectal examination (IV-C) [88]. Forpatients presentingwithasecondUTIepisodeorifaurinarytractabnor- mality issuspected (especiallyinpatients aged >50years), a urinarytractultrasoundwithpost-voidresidualmeasurement, aurologyconsultation,anddependingoncasesauroflowmetry arerecommended(healthcareprofessionalagreement).

Funding

TheseguidelineswerefundedbytheSPILF.

Acknowledgments

TheauthorswouldliketothankthemembersoftheGuideline StudyGroupoftheFrenchInfectiousDiseasesSociety(French acronymSPILF)fortheircriticalcommentsandforreviewing the presentguidelines:EricBonnet,Jean-PierreBru, Bernard Castan,RobertCohen,SylvainDiamantis,RémyGauzit,Benoît

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Key recommendations: male urinary tract infections

• Mandatoryurineculture.

• Possibility of differing the treatment of pauci- symptomaticmaleUTIs.

• Theuseofﬂuoroquinolonesandco-trimoxazole (SMX-TMP) must be preferred, even with multidrug-resistant bacteria – for prostate dif- fusionpurposes.

• 14daysoftreatmentinmostcases.

• Importanceofurologicalinvestigations.

Guéry, Thanh Lecompte, Philippe Lesprit, Laurence Maulin, YvesPéan,LionelPiroth,Jean-PaulStahl,ChristopheStrady, EmmanuelleVaron,FannyVuotto,andClaireWinterberger.

Theauthorswouldalsoliketothankthescientificsocieties towhichtheauthorsandtheGuidelineStudyGroupmembers wereaffiliated:Frenchurologicalassociation(Frenchacronym AFU),Frenchmicrobiologysociety(SFM),Frenchnationalcol- legeofteachersingeneralpractice(CNGE),Frenchradiology society(SFR),Frenchgynecologysociety(SFG),Frenchinfec- tious diseases group (GPIP) of the French pediatrics society (SFP),Frenchgeriatricsandgerontologysociety(SFGG).

Disclosureofinterest

Theauthorshavenotsuppliedtheirdeclarationofcompeting interest.

2. Versionfranc¸aise

2.1. Introduction

Cetteactualisationdesrecommandationsdepriseencharge desinfections urinaires(IU)bactériennescommunautairesde l’adulteaétéréaliséesousl’égide delaSociétédepathologie infectieusede langue franc¸aise(SPILF) avecdes experts des disciplinesconcernées:infectiologie,microbiologie,urologie, médecinegénérale,gériatrieetradiologie.

ConformémentàlaméthodologiedelaHAS[1]ungradeA, BouCaétéattribuéàchaquerecommandationselonleniveau de preuve scientifique attribué aux études sur lesquelles elle repose(Tableau1).Lorsquelesdonnéesdelalittératureétaient insuffisantes,lesrecommandationsrelevaientd’unaccordpro- fessionnelprenantencomptel’étatdespratiquesetlesopinions d’experts.

Les recommandations ont été mises en ligne sur le site de la SPILF (www.infectiologie.com) en 2014 (cystites ; pyélonéphrites;IUmasculines)puiscomplétées en2015(IU gravidiques;positionnementdelatémocillineetdutrimétho- prime[TMP]).Leprésenttextefaitlasynthèsedesprincipaux messages et intègre quelques modifications concertées en

Tableau1

Niveaudepreuveetforcedesrecommandations.

NiveauI GradeA

Essaicomparatifrandomisédegrandepuissance Méta-analyse

NiveauII GradeB

Essaicomparatifrandomisédefaiblepuissance

NiveauIII GradeC

Essaicomparatifcontemporainnonrandomisé Étudedecohorte

NiveauIV GradeC

Essaicomparatifavecunesériehistorique Sériedecas

2017afindetenircomptedel’actualisationdesrésistancesbac- tériennesauxantibiotiquesetdespublicationslesplusrécentes.

2.2. Terminologieetstratégiegénéraledepriseencharge Anciennement dénommées bactériuries asymptomatiques, les colonisations urinaires correspondent aux situations de présencedemicro-organismesdanslesurines,sansqueceux- ci negénèrent pareux-mêmesde manifestationscliniques,et qu’ilexisteounonuneleucocyturieassociée[2].Endehorsde lagrossesse,iln’yapasdenotiondeseuildebactériurie.

Les IU regroupentles différentes situations associant des signes cliniques – locaux ou généraux – et des signes biologiques:cystites,pyélonéphrites(PNApourpyélonéphrites aiguës), prostatites aiguës et autres formes d’IU masculines.

Seules lesformes aiguës sonticiabordées(parsoucidesim- plicité etconformémentaulangagemédical courant,leterme

«aiguë»n’estpassystématiquementrappelé).Cetexteconsa- cré auxinfectionsurinairesdel’adultepeutêtre appliquédès l’âgede16ans.

Pour guider laprise en charge(Fig. 1), la première étape devantunECBUpositifestdefairelapartentrecolonisationet infection.

En cas d’IU, il s’agit ensuite d’établir s’il s’agit d’une forme simple ou à risque de complication. Le terme d’IU à risque de complication estpréféré à l’ancienne dénomina- tion d’IU compliquée,car ils’agit desformes avecau moins un facteur de risque (FDR) pouvant rendre l’infection plus sévère ou plus difficile à traiter, sans que la complication ne soit nécessairement constituée. Les FDR de complication d’une IU sont d’une part toute anomalie organique ou fonctionnelle de l’arbre urinaire (résidu vésical, reflux, lithiase,tumeur,acteurologiquerécent...),etd’autrepartcer- tains terrains : sexe masculin, grossesse, sujet âgé ayant des critères de fragilité (cf. infra), insuffisance rénale chronique sévère(clairancedecréatinine<30mL/mn)etimmunodépres- siongrave(sansqu’il soitpossiblededéfinirprécisémentdes

« niveaux d’immunodépression à risque »). Sont considérés comme«sujetsâgésfragiles»lessujetsdeplusde75ans(au- delàtrèsraressontlessujetssansFDRdecomplication)etles sujetsdeplusde65anscumulantaumoins3critèresdefragilité selonlaclassificationdeFriedetal.[3]:pertedepoidsinvolon- taireaucoursdeladernièreannée,vitessedemarchelente,faible

(17)

Fig.1.Terminologieetstratégiedepriseenchargeglobale.

endurance,faiblesse/fatigueactivitéphysiqueréduite.Ainsi,par rapportauxprécédentesrecommandations,uneformedecritère d’âge est rétablie afin d’aider à identifier les sujets à risque d’évolutionmoinsfavorable.Acontrario,lediabèten’estplus considérécommeunFDRdecomplication:silesIUsontplus prévalentessur ce terrain,lescomplications nesont pasplus fréquentes.

PourlesIUavecsignessystémiques(IUautresquelescys- tites),ilconvientensuitederechercherl’existenceounond’un critèredegravité:

• gravitédusepsis:sepsisgrave(QuickSOFA≥2),chocsep- tique[4]

• ou nécessité d’un geste urologique (chirurgical ou inter- ventionnel autre qu’un simple sondage vésical) à risque d’aggravationdusepsisenpériopératoire.

Encasdecritèredegravité,ilconvientenfindedéterminer s’ilexisteounonunrisqueidentifiéd’IUàentérobactériespro- ductricesde␤-lactamasesàspectreélargi(E-BLSE),dufaitde l’impactimportantsurlechoixdel’antibiothérapieprobabiliste.

2.3. Outilsdiagnostiques 2.3.1. Bandeletteurinaire(BU)

LaBUn’apportequ’unevaleurd’orientationendétectantdes leucocytes,(seuildesensibilité:10⁴leucocytes/mm³),oudes

Messagesclés:terminologie

• DevantunECBUpositif,bienfairelapartentre colonisationetinfection.

• DevantuneIU:

◦ distinguerlesIUsimplesetcellesàrisquede complication

◦ identiﬁer les critères de gravité : niveau de gravité du sepsis, mais aussi geste urologiqueinvasif

◦ encasdegravitéprendreencomptelesfac- teursderisqued’infectionàE-BLSE

• LesIUmasculinesneserésumentpasauxpro- statites

nitrites, ces dernierssignant la présence d’uneentérobactérie (les autres microorganismesles plus fréquemment impliqués danslesIUneproduisentpasdenitrites)àfortedensité(virage delaréactionauseuilde10⁵UFC/mL).

LesperformancesdiagnostiquesdelaBUsontvariablesselon lesexe.Chezlafemmesymptomatique,l’intérêtdelaBUréside avanttoutdanssavaleurprédictivenégativeélevée(>95%)en l’absenced’immunodépressiongrave:danscecontexteuneBU négativedoitfairerechercherprioritairementunautrediagnostic [5].Chezl’hommesymptomatique,l’intérêtdelaBUrésideau