Comparison of different antibiotic protocols for asymptomatic bacteriuria in patients with neurogenic bladder treated with botulinum toxin A

brazjinfectdis2016;20(6):623–626

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Brief

communication

Comparison

of

different

antibiotic

protocols

for

asymptomatic

bacteriuria

in

patients

with

neurogenic

bladder

treated

with

botulinum

toxin

A

Ana

Claudia

Paradella

_,

_André

_Ferraz

_de

_Arruda

_Musegante

_,

_Carlos

_Brites

a_{SARAHNetworkofRehabilitationHospitals,Salvador,BA,Brazil}

b_{ComplexoHospitalarUniversitárioProfessorEdgardSantos,Salvador,BA,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received21March2016 Accepted2August2016 Availableonline18October2016

Keywords:

Botulinumtoxin,typeA Urinarytractinfections Bacteriuria

Antibioticprophylaxis

a

b

s

t

r

a

c

t

IntravesicalbotulinumtoxinA(BoNTA)injectionhasbeenwidelyusedforthetreatmentof detrusoroveractivityinpatientswithneurogenicbladderduetospinalcordinjurywhodo notrespondtoconventionaltreatment.Thereisnoconsensusaboutantibioticprophylaxis forthisprocedure.Weconductedaretrospectiveanalysisofmedicalrecordsofadultpatients withspinalcordinjurywhounderwentdetrusorBoNTAinjectionbetweenJanuaryof2007 andDecemberof2013inarehabilitationhospital.Occurrenceofsymptomaticurinarytract infection(UTI)wasassessedin3groupsinaccordancewiththeiruseofantibiotics (pro-phylacticdosage,3days,morethan3days)forthetreatmentofasymptomaticbacteriuria. Allpatientswereperformingselforassistedcleanintermittentbladdercatheterizationand underwentarigidcystoscopy,undergeneralorregionalanesthesiawithsedation,andthe drugusedwasBotox®_{.Atotalof616procedureswereperformedduringthestudyperiod.}

Therewere11identifiedcasesofUTI(1.8%)withatrendtoahigherrateinthegroupthat usedantibioticsforlongertime.Thisreportshowsthatasingledoseofantibioticsbefore thedetrusorBoNTAinjectionisenoughtopreventUTI.Randomizedclinicaltrialshouldbe conductedfordefinitiveconclusions.

©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Antimicrobialprophylaxisisthesystemicadministrationof antibioticsbeforeorduringsurgerywiththeintentof reduc-ingtheriskoflocalorsystemicinfectionaftertheprocedure. Thepotentialbenefitof antimicrobialprophylaxisis deter-minedbyfactorsinherenttothepatient, totheprocedure, andthepotentialmorbidityofinfection.Antimicrobial pro-phylaxisisrecommendedonlywhenthebenefitsoutweigh

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](C.Brites).

therisksandanticipatedcosts(includingcostofthe antibi-oticanditsadministration,riskofallergicreactionsorother adverseevents,andinductionofbacterialresistance).1_With

the growingproblemofbacterialresistance,the discussion ofantimicrobialprophylaxisand itsduration areextremely importanttopreventbacterialresistanceinducedby unnec-essaryuseofantibiotics.

http://dx.doi.org/10.1016/j.bjid.2016.08.012

1413-8670/©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

624

Antimicrobialprophylaxis inurologic endoscopic proce-duresisa controversialtopic.2,3 _{Astudy published in2013}

evaluatingtheuseofantibioticprophylaxisinurological pro-ceduresinEuropeobservedasignificantdiscrepancybetween practicesindifferentcountries,regions,andhospitalprofiles, aswell aspoor adherence to the publishedrecommended guidelines.4

DetrusorbotulinumtoxinAinjectionisanendourologic procedurewhichhasbeenwidelyusedforthetreatmentof overactivityinpatientswithneurogenicbladderduetospinal cordinjurywhodonotrespondtoconventionaltreatment.5

Theprocedureinvolvesinjectionsthatpenetratethemucosal barrier.6

TheguidelinesoftheAmericanandEuropeanurological associationsrefer toendourologicand transurethral proce-dures,butdonotmentioninjectionofbotulinumtoxininto thedetrusor.1,7_{Forthesekindofprocedures,themain}

com-plicationsarebacteriuria,urinaryinfectionand,morerarely, bacteremiaand sepsis.Asymptomatic bacteriuriafollowing endourologicproceduresgenerallyhasnoclinicalsignificance and mayspontaneously disappear.5,7,8 _{Asystematicreview}

thatassessedtheeffectivenessofantimicrobialprophylaxis inreducingtheriskofurinarytractinfectionintransurethral urologicproceduresevaluated 42studies,all ofwhich used the presenceofnegativeurine culturespriortothe proce-dureasinclusioncriteria.Patientswithneurogenicbladder wereexcluded.9_{Theonlystudywefoundassessingtheneed}

forantibioticprophylaxisinpatientswithneurogenicbladder fordetrusorBoNTAinjectionincludedpatientswithnegative urineculturesbeforetheprocedure.10

IntheguidelinespublishedbytheInfectiousDiseases Soci-etyofAmerica,itisclearthatthereisnoevidenceofbenefitin treatingasymptomaticbacteriuria.Asymptomaticbacteriuria (AB)ispresentinapproximately70%ofpatientswithspinal cordinjuryandneurogenicbladderwhoperformintermittent bladdercatheterization11_{duetofunctionalabnormalities,}

uri-narystasis,andthebladderemptyingtechnique.Thereisan indicationtotreatABonlyifthepatientexhibitsclinical symp-tomsofinfection.

Toassessthebenefitoftreatingasymptomaticbacteriuria inthepreventionofUTI,aretrospectivestudywasconducted inarehabilitationhospital,withevaluationofmedicalrecords ofpatientsadmittedfordetrusorBoNTAinjectionfrom Jan-uary2007toDecember2013.Patientsaged18yearsorolder withtraumaticandnontraumaticspinalcordinjury, perform-ingselforassistedcleanintermittentbladdercatheterization withasingle-usecatheterlubricated with2%xylocainegel wereincluded.Urineculturewithantibioticsusceptibilitytest wasperformed forall patients inthe firstday of hospital-izationusing midstream urine samplecollected byaseptic bladdercatheterization.Theexclusioncriteriawerethe appli-cation of BoNTA into the sphincter or other concomitant surgicalprocedure.

Patientswere divided into threegroupsforcomparative analysis,according tothe recommendationsofthe institu-tionalprotocol,whichguidedthemanagementofAB.From January2007 to February 2008, the protocol recommended theuseofantibioticsforsevendaysbasedontheresultsof urine culture,and the urologicalprocedure wasperformed onthefifthdayoftreatment(group1);from March2008to

March2009,therecommendationhaschangedtotheuseof antibioticsforthreedayswiththe procedureperformedon the second day oftreatment (group 2);from April 2009to December2013,therecommendationwastouseasingledose of antibiotic duringanesthetic induction(cefazolin as first option, ciprofloxacin assecond option)without taking into accounttheurineculture(group3).All patientswith nega-tiveurinespecimenshadasingleantibioticdose,regardless ofthetreatmentgroup.

AccordingtotheNationalInstituteonDisabilityand Reha-bilitationResearchquantitativeurine-culturecriteriaforthe diagnosisofasymptomaticbacteriuriaincludedcatheter spec-imens from individuals on intermittent catheterization in an amount equal to or greater than 102CFU/mL.11,12 _The

criteriaforsymptomaticurinarytractinfectionwerethe pres-ence ofbacteria incatheterspecimens fromindividuals in anamountequaltoorgreaterthan105CFU/mL,associated withatleastoneofthefollowingclinicalsymptoms, occur-ring within7seven daysofthe detrusorBoNTAinjection13_:

fever(temperaturegreaterthanorequalto37.8◦C);worsening ofneuropathicpainand/orspasticity;autonomicdysreflexia of unknown cause; increased urine loss between bladder catheterization;gastricsymptoms(nausea,vomiting,lossof appetite); lowerbackorsuprapubicpain;dysuria;antibiotic usefortreatmentofUTIwithinsevendaysoftheprocedure. Datafollowingdischargewerecollectedthroughactive search-ing(phonecall).Patientsweresubmittedtourineculture45 daysaftertheprocedure,whenreturningforoutpatient eval-uation.

All patientsunderwentarigidcystoscopyundergeneral orregionalanesthesiawithsedationandremained hospital-izedforatleast48h.ThedrugusedwasBotox®_{(AllerganInc.,}

Irvine,CA,USA),30applicationsof1mL(10internationalunits reconstitutedwithsaline),distributedthroughoutthebladder excludingthetrigone(totaldoseof300IU).Allprocedureswere performedbythesamesurgeon.

Demographicdataincludedgender,ageandtypeofinjury (traumatic or nontraumatic).Riskfactors investigatedwere hematuria and insertion of anindwelling urinary catheter (IUC)followingtheprocedure,previousdiagnosisofDiabetes mellitus, chronic use of corticosteroids, and smoking. The informationwasrecordedinadatabasedevelopedinACCESS 2003andanalyzedusingthestatisticalpackageSPSS.Absolute and relativefrequencieswereusedforcategoricalvariables andmeasuresofcentraltendencyanddispersionwereused forothers.Mann–WhitneyorKruskal–Wallistestswereused forvariableswithnonormaldistribution.Categoricalvariables wereanalyzedusingthechi-squaretestwithYates’correction, Fisher’sexacttestandthebinomialtest.p-Valueslessthan5% wereconsideredstatisticallysignificant.

A total of 616 procedures performed during the study periodon 487patients(1.3 procedures/patient)were evalu-ated:332(68%)weremale;themeanagewas37(±11.6)years; 321 (66%) patientshad atraumatic spinalcord injury, and 168 (34%) had a nontraumaticspinal cord injury (Table 1). Amongpatientswithatraumaticspinalcordinjury,26%had tetraplegiaand74%hadparaplegiaandinthegroupwitha nontraumaticspinalcordinjury,themostcommonconditions weremyelitis(38%),followedbyHTLVmyelopathy(25%),and myelomeningocele(10%).

brazj infect dis.2016;20(6):623–626

625

Table1–Demographics,riskfactors,andUTIdistributionwithinthepatientgroups.

Riskfactors Groups

Singledosage n=342 3days n=170 >3days n=104 p-Value Male,n(%) 227(66.4) 103(60.6) 61(58.7) 0.23a Meanage(SD) 36.6(11.1) 37(11.4) 35.4(10.7) 0.41b Traumatic,n(%) 238(69.6) 106(62.4) 64(61.5) 0.14a Hematuria,n(%) 100(29.2) 55(32.4) 38(36.5) 0.35a IUC,n(%) 73(21.3) 49(28.8) 67(64.4) <0.05a Diabetes,n(%) 6(1.8) 4(2.4) 4(3.8) 0.45a Corticosteroids,n(%) 2(0.6) 1(0.6) 1(1.0) 0.08c Smoking,n(%) 1(0.3) 3(1.8) 0(0) 0.52c UTI 5(1.5) 1(0.6) 5(4.8) 0.06d

IUC,indwellingurinarycatheter;UTI,urinarytractinfection.

a _{Chi-squaretestwithoutcontinuitycorrection.} c _{Chi-squaretestwithcontinuitycorrection.} b _{Kruskal–Wallistest.}

d _{Likelihoodratiochi-squaretest.}

Mostpatients(92%)hadasymptomaticbacteriuriabefore the procedure, while 8% had negative urine cultures. The mostcommonbacteria grownfrom urinespecimenstaken beforeandaftertheprocedurewereEscherichiacoli,followed byKlebsiellapneumoniae.Theprevalenceofmultidrugresistant bacteriaintheurineculturetakenbeforetheprocedurewas 7.3%;inthepostprocedureexamitwas9.3%.

We observed a difference with respect to the use of indwellingurethralcatheter(IUC)betweenthegroups,which wasmorecommoninthegroupthatusedantibioticsformore thanthreedays(p<0.05).Nopatientwasoncorticosteroidsor declaredtosmokeinthethreestudygroups(Table1).

Duringthestudyperiod,11casesofsymptomaticUTIwere identified:fiveinthegroupthattreatedbacteriuriaformore thanthreedays(4.8%),oneinthegroupthattreatedforthree days(0.6%),andfive(1.5%)inthegroupthatreceiveda sin-gledose.WedetectedatrendtohigherUTIratesinthegroup thatusedantibioticsforlonger time(≥3days),in compari-sonwith those thatused antibioticsforthree or lessdays (p=0.05). Nopatient had more than one symptomaticUTI event.Thesymptomsobservedinthepatientsthatdeveloped asymptomaticUTIwere fever and/orchills (81.8%), supra-pubicpain/discomfort (36.4%), urinaryincontinence (27.3%) and dysuria(9%). Nopatient had pyelonephritis,sepsis, or requiredintensivecare.Weobservednodifferencebetween frequency of symptoms for patients with clinical signs of infection,regardlessofdurationofantibioticuse.

Inconclusion,the majorityofpatientsinthis studyhad asymptomatic bacteriuria. The study reported 11 cases of symptomatic UTI (1.8%) with no difference between the groups,but withatendency forahigherrate inthegroup thatusedmorethanthreedaysofantibiotics(p=0.05).Most reportedclinicalsymptomswerefeverand/orchills.According totheriskfactors,onlytheinsertionofIUCsinpatientsthat usedantibioticsformorethanthreedaysshowedstatistical difference(p<0.05).

Thefindings ofthisstudy are inaccordancewith previ-ousreports,confirmingthatpatientswithspinalcordinjury whoperformintermittentbladdercatheterizationhavehigh ratesofasymptomaticbacteriuria.11,14 _{Thesepatients need}

toundergourologicproceduresfrequentlyandpreventingthe emergence ofmultidrug-resistant bacteria throughrational useofantibioticsisapriority.15_{Accordingtosomeexperts,the}

presenceofasymptomaticbacteriuriaisnota contraindica-tionforthedetrusorBoNTAinjectionandtheuseofantibiotic prophylaxis shouldfollow the normalroutineofeach hos-pitalsite.16 _{There are studies thatshow thata singledose}

ofantimicrobialhasbeeneffectiveandfeasibleforthe pre-ventionofpostoperativeinfection inurologicalsurgery.17 _A

study published in2010,10 _{with neurologicalpatients with}

sterileurineshowedaUTIrateof7.1%inpatientswhodidnot receive prophylacticantibioticfordetrusorbotulinumtoxin injection.Randomizedclinicaltrialssuggesthigherrates,but somestudies donotdistinguishbetweensymptomaticUTI andasymptomaticbacteriuria.Thisstudydescribesalow uri-narytractinfectionrateinalltreatmentgroups,suggesting thatasingle-doseofantibioticpreventsinfection complica-tionseveninpatientswithasymptomaticbacteriuria.

Risk factors for UTI include advanced age, smoking, anatomical and functional abnormalities, the use of corti-costeroids,immunosuppression,andurethralcatheters.The large majority of the patients evaluated in this study had asymptomatic bacteriuriaandtheriskfactors forUTIwere similar between the groups. The fact that the group that receivedantibioticsformorethanthreedaysinthisstudykept anIUCin64.4%aftertheprocedure,mayhavebeenrelatedto theteamexperience,sincewefoundthatthisratedecreased overtheyearswithoutrelationtocomplications.Theonly dif-ferencefoundbetweenthegroupswasrelatedtotheuseof antimicrobialsforlongerperiodsinpatientsthatusedanIUC. Inthesecases,wefoundatendencyforstatisticaldifference in the ratesofUTI incomparisonto the groupsthat used antibiotics forshorter periodsof time(p=0.05), suggesting thatexcessiveexposuretoantibioticsfavorstheoccurrence ofinfection.Nodifferenceswereobservedbetweengroupsfor theotherassessedriskfactors.

Incurrentpracticeupdatesprotocolsininstitutionsaimed at preventing microbial resistance induction generated by unnecessaryuse ofantibiotics, aswellasreducing adverse reactions, hospitalization time andcosts. Becauseit was a

626

non-randomized,retrospectivestudy,theexternalvalidityof thesedataarelimited.Anotherissueisthatthe487patients were submitted to 616 interventions, i.e. 20% of patients approximately participated in more than one group. The similarityinthepercentageofsymptomaticUTIafterthe pro-cedureinthethreegroupsmayhavebeenduetoapopulation undersimilarriskfurtheraggravatedbythelowincidenceof theoutcome(11intotal).

Ourresultsconfirmthattheuseofasingledoseof antibi-oticsbefore the detrusor BoNTA injectionin patients with asymptomaticbacteriuriaisenoughtopreventsymptomatic UTI.Itisnecessarytoconductarandomizedclinicaltrialto assesstheeffectofdifferentinterventionsforthe manage-mentofasymptomaticbacteriuriainpatientswithneurogenic bladderbeforedetrusorbotulinumtoxintypeAinjection.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1. AmericanUrologicalAssociationEducationResearch.Best practicepolicystatementonurologicsurgeryantimicrobial prophylaxis.Baltimore(MD):AmericanUrologicalAssociation EducationandResearch;2007.

2. BootsmaAM,LagunaPesMP,GeerlingsSE,GoossensA. Antibioticprophylaxisinurologicprocedures:asystematic review.EurUrol.2008;54:1270–86.

3. NaberKG,HofstetterAG,BruhlP,BichlerK,LebertC. Guidelinesfortheperioperativeprophylaxisinurological interventionsoftheurinaryandmalegenitaltract.IntJ AntimicrobAgents.2001;17:321–6.

4. CekM,TandogduZ,NaberK,etal.Antibioticprophylaxisin urologydepartments,2005–2010.EurUrol.2013;63:386–94.

5. CarneiroNetoJA,BittencourtVG,deOC,AndradeR,Carvalho EM.TheuseofbotulinumtoxintypeAinthetreatmentof

HTLV-1-associatedoveractivebladderrefractoryto

conventionaltherapy.RevSocBrasMedTrop.2014;47:528–32.

6.RovnerE.Chapter6:Practicalaspectsofadministrationof onabotulinumtoxinA.NeurourolUrodyn.2014;33Suppl 3:S32–7.

7.GrabeM,Bjerklund-JohansenTE,BottoH,etal.Guidelineson urologicalinfections.EuropeanAssociationofUrology;2013.

8.LinsenmeyerTA.Useofbotulinumtoxininindividualswith neurogenicdetrusoroveractivity:stateoftheartreview.J SpinalCordMed.2013;36:402–19.

9.AlsaywidBS,SmithGH.Antibioticprophylaxisfor transurethralurologicalsurgeries:systematicreview.Urol Ann.2013;5:61–74.

10.MouttalibS,KhanS,Castel-LacanalE,etal.Riskofurinary tractinfectionafterdetrusorbotulinumtoxinAinjectionsfor refractoryneurogenicdetrusoroveractivityinpatientswith noantibiotictreatment.BJUInt.2010;106:1677–80.

11.NicolleLE.Asymptomaticbacteriuria:reviewanddiscussion oftheIDSAguidelines.IntJAntimicrobAgents.2006;28Suppl 1:S42–8.

12.NicolleLE,BradleyS,ColganR,etal.InfectiousDiseases SocietyofAmericaguidelinesforthediagnosisandtreatment ofasymptomaticbacteriuriainadults.ClinInfectDis. 2005;40:643–54.

13.BennettJE,DolinR,BlaserMJ.Mandell,Douglas,and Bennett’sprinciplesandpracticeofinfectiousdiseases.8th ed.NewYork:Elsevier;2015.

14.ToganT,AzapOK,DurukanE,ArslanH.Theprevalence, etiologicagentsandriskfactorsforurinarytractinfection amongspinalcordinjurypatients.JundishapurJMicrobiol. 2014;7:e8905.

15.CameronAP,RodriguezGM,SchomerKG.Systematicreview ofurologicalfollowupafterspinalcordinjury.JUrol. 2012;187:391–7.

16.Jimenez-CidreMA,Arlandis-GuzmanS.OnabotulinumtoxinA inoveractivebladder:evidence-basedconsensus

recommendations.ActasUrolEsp.2015. pii:S0210-4806(15)00152-7.

17.TogoY,TanakaS,KanematsuA,etal.Antimicrobial prophylaxistopreventperioperativeinfectioninurological surgery:amulticenterstudy.JInfectChemother.