Pharmacodynamic profiling of commonly prescribed antimicrobial drugs against Escherichia coli isolates from urinary tract

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

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

Original

article

Pharmacodynamic

profiling

of

commonly

prescribed

antimicrobial

drugs

against

Escherichia

coli

_isolates

_from

_urinary

_tract

Gabriel

Trova

Cuba

_,

_Antonio

_Carlos

_Campos

_Pignatari,

_Katya

_Silva

_Patekoski,

Lucimila

Jorge

Luchesi,

Carlos

Roberto

Veiga

Kiffer

LaboratórioEspecialdeMicrobiologiaClínica,DepartmentofInfectology,UniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP, Brazil

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Articlehistory:

Received16August2013 Accepted23January2014 Availableonline13April2014

Keywords:

Pharmacodynamics MonteCarlomethod Escherichiacoli Urinarytractinfection

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Sinceantimicrobialresistanceamonguropathogensagainstcurrentfirstlineagentshas affectedthemanagementofsevereurinarytractinfection,wedeterminedthelikelihood thatantibiotic regimensachieve bactericidalpharmacodynamicexposuresusingMonte Carlosimulationforfiveantimicrobials(ciprofloxacin,ceftriaxone,piperacillin/tazobactam, ertapenem,andmeropenem)commonlyprescribedasinitialempiricaltreatmentof inpa-tients with severe community acquired urinary tract infections. Minimum inhibitory concentrationdeterminationbyEtestwasperformedfor205Braziliancommunityurinary tractinfectionEscherichiacolistrainsfrom2008to2012and74E.colibloodstreamstrains recoveredfromasurveillancestudy.Pharmacodynamicexposurewasmodeledviaa5000 subjectMonteCarlosimulation.Allisolatesweresusceptibletoertapenemandmeropenem. Piperacillin/tazobactam,ceftriaxoneandciprofloxacinshowed100%,97.5%and83.3% sus-ceptibilityamongoutpatientisolatesand98.6%,75.7%and64.3%amonginpatientisolates, respectively.Againstoutpatientisolates,alldrugsexceptciprofloxacin(82.7%inaggressive and77.6%inconservativescenarios)achievedhighcumulativefractionofresponse: car-bapenemsandpiperacillin/tazobactamcumulativefractionofresponseswerecloseto100%, andceftriaxonecumulativefractionofresponsewas97.5%.Similarresultswereobserved againstinpatientsisolatesforcarbapenems(100%)and piperacillin/tazobactam(98.4%), whereasceftriaxoneachievedonly76.9%bactericidalcumulativefractionofresponseand ciprofloxacin61.9% (aggressivescenario)and56.7% (conservativescenario)respectively. Basedonthismodel,standarddosesofbeta-lactamswerepredictedtodeliversufficient pharmacodynamicexposureforoutpatients.However,ceftriaxoneshouldbeavoidedfor inpatientsandciprofloxacinempiricalprescriptionshouldbeavoidedinbothinpatients andoutpatientswithcomplicatedurinarytractinfection.

©2014ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthor.}

E-mailaddress:gbtrova@gmail.com(G.T.Cuba).

http://dx.doi.org/10.1016/j.bjid.2014.01.008

Introduction

Urinarytract infection(UTI) isthe mostcommonbacterial infectionandacutepyelonephritisisasevereformofUTIwith symptomsthatrangefrommilddiscomforttolifethreatening illness or death.1,2 _{The incidence of pyelonephritis} requir-inghospitalizationis3–4casesper10,000populationamong womenand1–2casesper10,000populationamongmen,with anestimation ofdirectandindirect costsofUS$2.1billion andinhospitalmortalityof7.3per1000hospitalizationsfor femalesand16.5 per1000formales.2–4 _{Thebacteriologyof} pyelonephritisissimilar tothe other UTIs, themajority of thembeingcausedbyEscherichiacoli.3,5

Themanagement ofUTIs isusuallyempirical,basedon thepredictable spectrumofetiologicagents andtheir sus-ceptibilitypatterns.Due tothe emergence ofantimicrobial resistanceamonguropathogens,thesafetyandeffectiveness ofempirical therapyhave been affected.6 _{Recently,ex vivo} pharmacodynamic(Pd)models(basedonMonte Carlo sim-ulation)havebeenusedtohelpdeterminethebestregimens ordosagesforaspecificpatientpopulation,byintegratingan agent’sinvitropotencydistribution(i.e.,minimuminhibitory concentrations[MICs])withthepharmacokinetic(Pk)profile ofadrug.7

Regional surveillance studies show that antimicrobial resistance against currently prescribed first line agents (trimethoprim/sulfamethoxazoleandciprofloxacin)for treat-mentofcommunityacquiredUTIsinBrazilisincreasing.8,9 Since the resistance patterns of E. coli strains caus-ing UTI vary considerably between regions and countries, specific treatment regimens based on local susceptibil-ity patterns are necessary.5,9 _{The aim of this study was} to compare the pharmocodynamic profiles of five antimi-crobials(ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenemandmeropenem)commonlyprescribedasinitial empirical therapy in hospitals for the treatment of inpa-tientswithcommunityacquiredUTIs,usuallycomplicatedor pyelonephritis.

Materials

and

methods

Microbiology

Bacterialisolates

Thepresentstudyincludedatotalof279bacterialisolates;100 isolatesofoutpatientsstoredattheculturecollectionofthe SpecialLaboratoryofClinicalMicrobiology(LEMC)since2008, 105isolates ofoutpatientsprospectively collected between AugustandNovember2012,and74nosocomialisolatesfrom thefirstbacteremiaat16 hospitalsinBrazilparticipantsof theBrSCOPEstudy.10_{AllisolateswereidentifiedwiththeBD} Phoenix 5.1TM (BectonDickinson, Sparks, MD 21152, USA) and/orbiochemicalidentificationmethods.Onlyoneisolate perpatientwasincludedinthestudy.

Minimalinhibitoryconcentration(MIC)testing

The MIC was determined by epsilometric test (Etest®_, BioMérieux,Marcyl’Etoile,France)forertapenem(0.002–32),

meropenem (0.002–32), ciprofloxacin (0.002–32), ceftriaxone (0.016–256)andpiperacillin/tazobactam(0.016–256),following the recommendations ofthe manufacturer.Qualitycontrol wasperformedbytestingE.coliATCC25,922®_{andP.aeruginosa} ATCC®_{27,853,withallresultswithinexpectedranges.}

Samplesweresubculturedontobloodagarandthenonto MacConkey agar to ensure viability and purity. Individual colonieswerepickedfrom18to24hplatesandsuspendedin 0.85%salinetoaturbidityofa0.5McFarlandstandard.Cotton swabswereusedtotransfertheinoculumtotheplateswith MuellerHinton agar(Oxoid,Basingstoke, Inglaterra), which were driedbefore the Etest® _{strips were applied. For each} strain, the fiveantibiotics were arranged ina singleplate. Plateswereincubatedfor18–24hat35◦_{C.Readingsand}

inter-pretationswereperformedaccordingtoNationalCommittee forClinicalLaboratoryStandards(NCCLS).11

PkandPddata

Pkdata

Pkdatawereobtainedfrompreviouslypublishedstudiesin healthyvolunteers.12–14_{Forstudiestobeconsidered,theyhad} to beconductedinatleast 10 healthy volunteers, describ-ing the assay used to determinedrug concentrations, and presentmeanandstandarddeviationresultsforthetotalbody clearanceinlitersperhour(CL),volumeofdistributionofthe centralcompartment(Vc)andotherpertinentPkparameters. Becausepublishedreportswiththeabovecharacteristicswere notidentifiedforpiperacillin/tazobactamandceftriaxone,Pk dataforthesedrugsweretakenfrompublishedstudies15,16_in criticalpatients(nostudiesdescribingthecovariancematrix inhealthyvolunteers).ThePkdatawasthenusedintheMonte Carlosimulationmodels.A5000patientMonteCarlo simula-tion(OracleCrystalBallFusionEdition,2010)wasconductedto calculateestimatesoftheamountoftimeinwhichthefreeor non-protein-bounddrugconcentrationexceedstheMICofthe organism(fT>MIC)ortheAUC/MICratioforeachantibiotic regimen/bacterialpopulation combination.Thesimulations were conductedas previouslypublished.17,18 _Drugdosages chosen were based on the following commonlyprescribed regimens,administeredas30-minintravenous(IV)infusions: ertapenem 1g every 24h (q24h), meropenem 1g every 8h (q8h),piperacillin/tazobactam4.5gevery8h(q8h),ceftriaxone 1gevery12h(q12h)andciprofloxacin400mgevery12h(q12h). Pdexposures,asmeasuredbyfT>MIC,weresimulatedforall beta-lactamregimensagainstallpathogengroups.Atwo com-partmentIVbolusequationwasusedtocalculate%fT>MIC forthebetalactams.Forciprofloxacin,thetotaldrugAUCwas calculatedasthedailydosedividedbythetotalbodyclearance (ClT).

Pdmodel

Table1–MICdistributionforoutpatientE.coli_{(OEC)andinpatient}E.coli_{(IEC)includedinthisstudy.}

Bacterialgroup(n)andantimicrobial Percentage(%)ofbacteriaateachMICvalue(mg/L)

0.008 0.016 0.032 0.06 0.125 0.25 0.5 1 2 4 8 16 32 >32

OEC(205)

Ertapenem 88 10 1 0 0 1 0 0 0 0 0 0 0 0

Meropenem 12 87 1 0 0 0 0 0 0 0 0 0 0 0

Ceftriaxone 2 4 58 24 9 1 0 0 0 0 1 0 0 1

Piperacillin/tazobactam 0 0 0 0 0 0 2 24 63 10 1 0 0 0 Ciprofloxacin 35 37 1 3 0 6 1 1 0 1 1 14 0 0

IEC(74)

Ertapenem 74 18 4 4 0 0 0 0 0 0 0 0 0 0

Meropenem 14 79 6 0 1 0 0 0 0 0 0 0 0 0

Ceftriaxone 0 13 46 13 0 1 0 1 1 3 4 7 3 8

Piperacillin/tazobactam 0 0 0 0 0 1 0 29 56 13 0 0 0 1 Ciprofloxacin 27 26 3 0 0 6 3 0 0 0 6 3 26 0

previouslyproposed as Pd thresholdfor UTI. Microbiologi-calcurewereachievedattainingacumulativefT>MICabove 30h.19 _{The probability for achieving a total AUC/MIC ratio} greaterthanorequalto62.5,75,100,125,and150were cal-culatedforciprofloxacin.ThePdtarget ofAUC/MICatleast 62.5(conservativescenario,halfofthetargetforbloodstream infection)and125(aggressivescenario,similartothetarget forbloodstreaminfection)werechosenasaPdbreakpointfor ciprofloxacin.These probabilitiesoftarget attainmentwere appliedtotheMICdistributionsfortheabovepathogensto calculatethecumulativefractionofresponse(CFR).

Results

Invitroactivity

Table 1 summarizes the results of the in vitro

suscepti-bility testing. The resistance profile of outpatient isolates from2008to2012wassimilar.Allisolatesweresusceptible toertapenemandmeropenem(MICrange 0.008–0.25␮g/mL and MIC range 0.008–0.032␮g/mL, respectively); 100% of outpatient isolates (MIC range 0.5–8␮g/mL) and 98.6% of inpatient isolates (MIC range 0.25–256␮g/mL) showed sus-ceptibilitytopiperacillin/tazobactam.Higherresistancerates against ceftriaxone were observed for inpatient E. coli

(75.7%susceptibility,MICrange0.016–256␮g/mL)when com-pared to outpatient E. coli (97.5% susceptibility, MIC range 0.008–256␮g/mL).Amongtheantibioticstested,ciprofloxacin had the lowest susceptibility rates against the outpatient E.coli(83.3%,MICrange0.008–0.032␮g/mL)andinpatientE.coli (64.3%,MICrange0.008–32␮g/mL).

Pdtargetattainment

TheProbabilityofTargetAttainment(PTA)forbeta-lactams andciprofloxacinoverarangeofMICsisindicatedinFig.1. TheCFRsforeachbeta-lactamatvaryingtargetsfor%fT>MIC arelistedinTable2andtheCFRforciprofloxacinatAUC/MIC target of 62.5–150 is presented in Table 3. Carbapenems demonstrated high likelihood ofachieving the bactericidal breakpointof40%fT>MICandpiperacillin/tazobactamat50% fT>MICinbothscenarios.Incontrast,ceftriaxoneachieved a CFR superior to 95% only against outpatient isolates. CiprofloxacinhadpoorCFRagainstoutpatient(82.7%,77.6%) andinpatient(61.9%,56.7%)isolatesatthetargetexposureof totalAUC/MIC>62.5andAUC/MIC>125,respectively.

Considering a treatment duration of seven days, the cumulative fT>MIC superior to 30h was achieved at MIC concentration of 8␮g/mL for ceftriaxone, 8␮g/mL for meropenem, 1␮g/mL for ertapenem and 64␮g/mL for piperacillin/tazobactam.

Table2–Cumulativefractionofresponse(CFR)atvarying%fT>MICforbeta-lactamsagainstoutpatientE.coli_and

inpatientE.coli_{isolatesfromBrazil.}

Isolates(no.)/antimicrobial CFRatvarying%fT>MICexposures

20% 30% 40% 50% 60% 70% 80% 90% 100%

OutpatientE.coliisolates(205)

Ertapenem1gq24h 100% 100% 99.99% 99.75% 99.53% 99.51% 99.27% 98.42% 98.81% Meropenem1gq8h 100% 100% 100% 100% 100% 100% 100% 100% 100% Ceftriaxone1gq12h 98.03% 97.91% 97.72% 97.50% 96.09% 92.49% 86.64% 79.37% 74.24% Piperacillin/tazobactam4.5gq8h 100% 100% 99.99% 99.87% 98.87% 97.88% 95.27% 93.05% 90.11%

InpatientE.coliisolates(74)

100%

90%

80%

70%

60%

40% 50%

30%

20%

10%

Ciprofloxacin

Ceftriaxone

Ertapenem

Meropenem

Piperacillin Tazobactam

0%

0,008 0,016 0,032 0,06 0,125 0,25

0,5 1 2 4 8 16 32 64 _{128 256}

Fig.1–ProbabilityofTargetAttainment(PTA)forbeta-lactamsandciprofloxacinoverminimuminhibitoryconcentration

(MIC).

Discussion

Increasing rates of resistance to antimicrobials commonly usedfortreatingUTIscausedbyE.coliamongoutpatientshas been reportedinrecent years.20 _{Inthis context,this study} compared the antimicrobial susceptibility of community-acquiredUTIE.colistrainsbetweentwoperiods,sincelocal susceptibilitypatternsareessentialforappropriate antimicro-bialprescribing.Thestudyalsoincludednosocomialisolates fromthefirstbacteremiaepisode.Despitehighvariabilityin theorigin ofbacteremiareportedin theliterature,the uri-nary tract is one of the most frequent sources for E. coli bacteremia.21 _{For this reason, the authors considered the} inclusionoftheseisolatesinthestudyasrelevant.

The sensitivity profile of outpatient E. coli was similar between 2008 and 2012. For ciprofloxacin, local surveil-lance studies on uropathogens in community-acquired infections9,22 _{also found decreased susceptibility pattern} of outpatient E. coli, especially since the year 2000. Our present results are similar to those described locally by Rochaetal.,22 _{whichobtained82.2%inisolatesof2009.For} otherantimicrobialstested,our studyshowedresults simi-lartotheSENTRYstudy:lowprevalenceofceftriaxoneand piperacillin/tazobactamresistanceandnoresistanceagainst carbapenems.9

The Monte Carlo Simulation has already been used to forecast the efficacy of different therapeutic regimens

in multiple scenarios, such as bloodstream infections, community-acquired pneumonia and ventilator-associated pneumonia.17,23,24_{Tothebestofourknowledge,ourstudyis} thefirstreporttoapplytheMonteCarloSimulationevaluating thelikelihoodofachievingbactericidalPdtargetsinUTIs.

AsforthePdtargetsadopted,fewstudieshaveestablished specificPdthresholdsforUTI.Deguchietal.,25_{determinedthe} Pdtargetoflevofloxacinformicrobiologicalcureinpatients withcomplicatedUTIbasedontheplasmaconcentrationof thedrugandthethresholdofAUC/MICforpredicting microbi-ologicalcurewaslowerthanthoseinotherkindofinfections. NostudiescorrelatingaPdtargetofciprofloxacinplasma concentration andmicrobiological cureforUTIwere found inourreview.Sinceciprofloxacinand levofloxacinare fluo-roquinolonesandtargetswithinantibioticclassestendtobe similar,weproposedthetwoscenariospreviouslydescribed: anaggressiveandaconservativeoneforciprofloxacin.

With respect to beta-lactam antibiotics, a cumulative fT>MICaround 30hwas correlated tomaximumcurerate forserumaminopenicillinconcentration.19_{Unfortunately,no} study correlating microbiological cureforUTI and fT>MIC ratio for meropenem, ertapenem, piperacilin/tazobactam and ceftriaxone were found. Considering the target for aminopenicillinsimilartothe drugsincludedinthisstudy, those resultsmight not beapplicable on real lifescenario sincean 8␮g/mL MIC formeropenem and a64␮g/mL MIC for piperacillin/tazobactam would be considered interme-diate based on CLSI breakpoints, and a 16␮g/mL MIC for

Table3–Cumulativefractionofresponse(CFR)forvaryingtotalAUC:MICforciprofloxacin400mgq12hagainst outpatientE.coli_andinpatientE.coli_{isolatesfromBrazil.}

Isolates(no.) CFRatvaryingtotalAUC:MICexposures

62.5 75 100 125 150

OutpatientE.coli(205) 82.71% 82.32% 80.05% 77.63% 76.76%

ceftriaxone,resistant.Forrenaltissueinfection,theserumor plasmaconcentrationisausefulmarkerfortheantibiotic con-centrationsintherenaltissue.19_{AsPdtargetsforbeta-lactams} insevereUTIarenotwellelucidated,forthepresent simu-lationweconsideredtheestablishedtargetsforbloodstream infections.

Initially,weestimatedthevariabilityforthePkparameters derivedfromhealthyvolunteers.Pkdatafromcriticalpatients werechosenforpiperacillin/tazobactamandceftriaxonedue toalackofpublishedreportswhichmettheinclusion crite-riaforourstudy.DeRykeetal.,18_{foundCFRlargelysimilar} forpiperacillin/tazobactam whetherPkofpatientsorthose ofhealthyvolunteerswereused.Concerningceftriaxone,in spiteofaweakincreaseofVcandwideinter-patient variabil-ityobservedincriticalpatients,totalserumconcentrations weresimilartothatobservedinnormalpatients.26

Current recommendation advises not to prescribe ciprofloxacinasempiricaltreatmentforUTIiflocalresistance exceeds 10%.5 _{Surveillance studies had already} demon-strated that ciprofloxacin resistance in Brazil overcomes suchpercentage.18,19_{Ourstudycorroboratesepidemiological} findings,whichimpactsonalowprobabilityofachievinga bactericidalexposure(CFRof77.6%foroutpatientsand56.7% forinpatientsconsideringanAUC/MICtargetofatleast125). EveniflowerPdtargetswerechosen,CFRstayedconsistent (≤5%decreases).

BasedonthesimulatedPTAsciprofloxacinshouldbe pre-scribedonlywhenMICwasequalorbelow0.25␮g/mL,despite the susceptibility thresholdcurrently considered. Inconsis-tency between susceptibility and the predicted efficacy of antimicrobialshasalreadybeenreportedsinceCLSI-defined breakpointsforGramnegativebacillimightoverestimate sus-ceptibilityintwotofourfoldgreaterthanthoseestimatedby Pdsimulations.27

CeftriaxoneisagoodoptiontotreatsevereUTIinfectionin outpatientsbasedonoursimulations.Although dissemina-tionofclonesproducingESBLofcommunity-acquiredE.coli infectionswerealready reportedintercontinentally,8_almost all outpatient isolates were susceptible to ceftriaxone. We observedahighpercentageofnon-susceptibilityagainst cef-triaxone (25.7%) in inpatientisolates, which decreases the probabilityofachieving bactericidal exposures(76.9%)with thisregimen.

Inthisanalysis, piperacillin/tazobactam,ertapenemand meropenemachievedthehighestCFRsinbothscenarios. Pre-viousPk/Pdstudiesalsofoundahighlikelihoodofachieving optimal Pd target exposure for meropenem against E. coli isolates.17,18,27

Similar to the derived result from Pd simulation of ciprofloxacin, ertapenem presented a fourfold discrepancy between CLSI defined breakpoint and those derived from stochastic determination. Althoughertapenem had similar invitroactivitytomeropenem,itsabilitytoachievehigh bac-tericidalPdexposurewilldependonthepresenceofahighly susceptiblepopulation,17_{whichwasreportedinthisstudy.}

InspiteofhighCFRobservedinpresentstudy,lowerCFRsof piperacillin/tazobactamagainstE.coliisolateswaspreviously demonstrated.24_{Beta-lactam/beta-lactaminhibitor} combina-tionisaneffectiveoptiontotreatESBL–E.colibloodstream infection originating from the urinary tract and should be

consideredareasonablealternativetocarbapenemsifactive invitro.21

Certainassumptionsaremadeforanalysesperformedwith MonteCarlosimulations.First,althoughtheresistancerates inourstudyweresimilartoprevioussurveillancestudies,it maynotreflectisolatefrequencyand/orsusceptibilitiesatall institutions.Second,weusedPkmodelsderivedfromhealthy andinfectedadultpatients,mostofwhomhadnormalrenal function.Doseadjustmentsmightbenecessarytoattain sim-ilar resultsforpatientswithrenalinsufficiencyorpediatric population.Finally,furtherstudiesare requiredtoelucidate thePdthresholdforciprofloxacinandbeta-lactamsnecessary toprovidemicrobiologicalcureinUTIs.

Onthebasisofthismodelusingmicrobiologydatafrom outpatientandinpatienturinaryisolates,standarddosesof beta-lactamswerepredictedtodeliversufficientPdexposure foroutpatients.Incontrast,thelowprobabilitypredictedfor ceftriaxonesuggeststhatthisdrugshouldnotbeprescribed inpatientswhohavehistoryofrecenthospitalization,early onsetofin-hospitalE.colibacteremiaorareinclose relation-shipwithhealthcareunits.Ciprofloxacinprescriptionshould bediscouragedevenincommunity-acquiredsevereITU.

Funding

This study was supported by Merck Sharp & Dohme. The pharmaceuticalcompanywasneitherinvolvednorhadany interferencewithdatacollection,interpretationoffindingsor preparationofthemanuscript.

Ethical

approval

ThisstudywasapprovedbytheEthicsCommitteeof Univer-sidadeFederaldeSãoPaulo(UNIFESP).

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

Thisstudywaspartiallypresentedasanabstractatthe23rd European Congress of Clinical Microbiology and Infectious Diseases,2013(abstract2872).

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