New Bugs? New Drugs! - MSHP Homemshptx.org/uploads/3/4/1/8/34180063/crystal_howell_-_final.pdf ·...

NewBugs?NewDrugs!CRYSTAL HOWELL , PHARMD, BCPS

UNIVERS ITY OF NORTHTEXAS HEALTHSC IENCE CENTER

MEDICAL C ITY DALLAS

CRYSTAL .HOWELL@UNTHSC .EDU

Alongtimeago,inagalaxyfar,faraway………

TheMicroorganismsStrikeBack•Urgentthreat• Clostridiumdifficile• Carbapenem-resistantEnterobacteriaceae• Drug-resistantNeisseriagonorrhoeae

•Seriousthreat• Multi-drugresistantAcinetobacter• Drug-resistantCampylobacter• Fluconazole-resistantCandida• Extendedspectrumβ-lactamaseproducingEnterobacteriaceae (ESBLs)• VancomycinresistantEnterococcus (VRE)• Multi-drugresistantPseudomonasaeruginosa• Drug-resistantnon-typhoidal Salmonella• Drug-resistantShigella• Methicillin-resistantStaphylococcusaureus(MRSA)• Drug-resistantStreptococcuspneumoniae• Drug-resistanttuberculosis

https://www.cdc.gov/drugresistance/biggest_threats.html

LearningObjectives1. ReviewrecentlyFDAapprovedantimicrobialsandantimicrobialsin

thepipeline

2. Discussappropriateuseofnewantimicrobialagentsandtheirnicheintherapy

3. Assessvarioustreatmentoptionsforpatientcases

ANewHope?RECENTLYAPPROVED

•2015• Ceftazidime-avibactam• Isavuconazonium sulfate

•2016• Obiltoxaximab• Bezlotoxumab

•2017◦ Meropenem/vaborbactam*◦ Delafloxacin*◦ Ozenoxacin*◦ Secnidazole

PHASE3CLINICALTRIALS

• Cadazolid• Cefiderocol*• Ervacycline• Iclaprim*• Imipenem/cilastatin/relebactam*• Lefamulin*• Omadacycline• Plazomicin• Zolithromycin• Fusidic acid• Zabofloxacin

https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdfhttp://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics

FDAApprovedAntibacterials

Meropenem/vaborbactam(Vabomere™)•Indication:complicatedUTIinadultsincludingpyelonephritis• Qualifiedinfectiousdiseaseproduct:cUTI,IAI,HABP,VABP,NF,andCRBSI

•Mechanismofaction:• Meropenem– bindstoPBPtoinhibitcellwallsynthesis• Vaborbactam– non-suicidalβ-lactamaseinhibitor

•Dose:4g(2gmeropenemand2gvaborbactam)IVover3hrsq8h• Renaladjustmentrequiredforbothmeropenemandvaborbactam

Vabomere™.[Packageinsert].Parsippany,NJ:TheMedicinesCompany;2017

Meropenem/vaborbactamIndicatedBacteria PossibleBacteria

Enterobacter cloacaespeciescomplex CitrobacterfreundiiEscherichiacoli Citrobacterkoseri

Klebsiellapneumoniae EnterobacteraerogenesKlebsiellaoxytoca

MorganellamorganiiProteusmirabilis

ProvidenciaspeciesPseudomonasaeruginosa

Serratiamarcescens


AmblerClassificationClass ActiveSite Enzyme Type Example

A Serine - Penicillinase- BroadSpectrum- Extended-Spectrum- Carbapenemase

- TEM1,SHV-1inE. coli andK.pneumoniae

- CTX-MinP.aeruginosa- KPC-1 inK.pneumoniae

B Metallo-β-lactamases(Zn2+)

- Carbapenemase - NDM-1inEnterobacteriaceae

C Serine - Cephalosporinase - AmpCinEnterobacteriaceae

D Serine - Broad-Spectrum- Extended- Spectrum- Carbapenemase

- OXA- family inP.aeruginosa

MOLECULARMECHANISMSOFANTIBIOTICRESISTANCEINBACTERIA.INMANDELL,ED.PRINCIPLESANDPRACTICEOFINFECTIOUSDISEASES.8TH ED.BLAIRJM,ETAL.NATURE 2015;13:42-51MAYOCLIN PROC 2011;86(3):250-259MAYOCLIN PROC 2015;;90(3):395-403

Amp-C•Primarilychromosomal

•Commonorganisms:◦Morganella morganii◦ Yersiniasp.◦ Serratiasp.◦ Providenciasp./Pseudomonassp./Proteussp.◦ Acinetobactersp./Aeromonassp.◦ Citrobacterfreundii◦ Enterobactersp.

OpalS,Pop-Vicas A.MolecularMechanismsofAntibioticResistanceinBacteria.InMandell,ed.PrinciplesandPracticeofInfectiousDiseases. 8th ed.BlairJM,etal.Nature 2015;13:42-51Kanj S,Kanafani Zeina.MayoClin Proc 2011;86(3):250-259VasooMayoClin Proc2015;;90(3):395-403

Meropenem/vaborbactam•SusceptibilityInterpretationformeropenem/vaborbactam

•β-lactamaseactivity• EffectiveagainstKPC,SME,TEM,SHV,CTX-M,CMY,andACT• NOTactiveagainst:metallo-β-lactamasesoroxacillinaseswithcarbapenemaseactivity

S I R

Enterobacteriaceae ≤4/8 8/8 ≥16/8


Meropenem/vaborbactam•PK/PD:• PK:

• PDparameter:• Meropenem:timeoverMIC• Vaborbactam:AUC:MIC

• Meropenemandvaborbactamareremovedbydialysis

Parameter Meropenem Vaborbactam

Cmax (mg/L) 57.3(23) 71.3(28.6)

CL(L/h) 10.5(6.4) 7.95(4.3)

AUCss (mg*h/L) 650(364) 835(508)

T1/2 (h) 2.3(2.5) 2.25(2.1)


Tango1- Methods•StudyDesign:• Phase3,multicenter,double-blind,double-dummy,randomizedcomparingmeropenem/vaborbactamvspiperacillin/tazobactam inthetreatmentofcUTIandacutepyelonephritis

•Intervention:• Meropenem/vaborbactam4gIVover3hrsq8hvspiperacillin/tazobactam4.5gIVover30minq8hfor10-14d

• After5daysallowedtoswitchtolevofloxacin

•Outcomes:• Primary:m-MITToverallsuccessatendofIVtherapy• Overallsuccess=clinicalcureorimprovementanderadicationofbaselinepathogento<104

CFU/mL

UnpublishedinformationrequestfromTheMedicinesCompany

Tango1- Results

CI=confidenceinterval;EOIVT=endofintravenoustreatment;m-MITT=MicrobiologicalModifiedIntent-to-Treat,ME=microbiologicalevaluable;TOC=TestofCure.*PerFDAcriteria,amicrobiologicoutcomeofEradicationisdefinedasthedemonstrationthatthebacterialpathogen(s)foundatbaselineisreducedto<104CFU/mLofurine.**PerEMACriteria,amicrobiologicoutcomeofEradicationisdefinedasthedemonstrationthatthebacterialpathogen(s)foundatbaselineisreducedto<103CFU/mLofurine.Overallsuccess=clinicaloutcomeofcureorimprovementandmicrobiologicoutcomeoferadication.


Tango1– Resultsbypathogen

Tango2•StudyDesign:• Phase3,multicenter,open-label,randomizedtrialofadultpatientswithCREseriousinfectionsandananticipated7daysofIVtherapy• Seriousinfection:bacteremia,cUTI,AP,HABP,VABP,cIAI

•Intervention:• Meropenem/vaborbactam4gIVover4hrsq8hvsbestavailabletherapy• ExcludedpatientswithclassBmetallo-β-lactamasesorclassDoxacillinases

•Outcomes:• ProportionofpatientswithclinicalcureatEOTandTOC• AllcausemortalityatDay28


Tango2- Results


Wheredoesvaborbactamfitin?ESBLproducer Amp-C

producerCarbapenamase

Ampicillin-sulbactam R R R

Piperacillin-tazobactam V R R

Ceftazidime-avibactam S S V

Ceftolozane-tazobactam S S V

Aztreonam-avibactam S S V

Meropenem-vaborbactam V S V

MayoClin Proc 2015;90(3):395-403UnpublishedinformationrequestfromTheMedicinesCompany

R=resistantS=sensitiveV=variable

PotentialNiche?•Additionaltrialsonclinicaltrials.gov• HABP/VABP– notyetrecruiting• Dosefindingstudyforseriousbacterialinfectionsinpediatrics- recruiting• SeriousinfectionsduetoCREinadults- completed

•Clinicalthoughts• Sinceitdoesn’tcovermetallo-β-lactamaseswouldlikesusceptibilitiespriortouse

• Forhospitalsnotdoingextendedinfusions,thisdrugcouldbeagatewayforotherextendedinfusionβ–lactams

• InterestingthatthecoverageforEnterobactersp wassomuchlowerthanpiperacillin-tazobactam whenβ-lactamaseswerepresent

• Wouldreservethisdrugformulti-drugresistantgramnegativeorganismswithsusceptibilities

Delafloxacin(Baxdela™)•Indication:acutebacterialskinandskinstructureinfections(ABSSSI)•Mechanismofaction:inhibitsbothtopoisomeraseIVandII• InhibitsDNAreplication,transcription,repaid,andrecombination

•Dose:• IV:300mgIVq12hover60minx5-14d• eGFR 15-29:300mgq14hORswitchtoPOafterIVdose,notrecommendedforeGFR <15

• PO:450mgPOq12hx5-14d• Nodoseadjustmentforrenaldisease,notrecommendedforeGFR <15

• Switching:300mgIVq12hover60minthenswitchto450mgPOq12hatthediscretionofthephysicianfor5-14d

•Warnings• Tendinitis,tendonrupture,peripheralneuropathy,centralnervoussystemeffects,exacerbationofmyastheniagravis,andCDI

• NoQTcwarning

Baxdela™.[PackageInsert].Lincolnshire,Illinois:Melinta Therapeutics;2017

DelafloxacinGramPositive Bacteria GramNegativeBacteria

Staphylococcus aureus(includingMSSAandMRSA)

Escherichiacoli

Staphylococcus haemolyticus KlebsiellapneumoniaeStaphylococcus lugdunensis EnterobactercloacaeStreptococcuspyogenes PseudomonasaeruginosaStreptococcusagalactiae Enterobacteraerogenes*

Streptococcusanginosus group Haemophilusparainfluenzae*Enterococcus faecalis Klebsiellaoxytoca*

Streptococcusdysgalactiae* Proteus mirabilis**Efficacyintreatingclinicalinfectionswiththeseorganismsisunknown


Delafloxacin


Delafloxacin•PK/PD:• PK:

• Distribution:30-48L(~TBW)• MetabolismthroughUGT1A1,UGT1A3,UGT2B15

• PDparameter:AUC:MIChoweverthePIalsonotesthatithasaconcentrationdependentbactericidalactivityinvitro

Parameter Tablet SteadyState IVSteadyState

Cmax (mg/L) 7.45 9.29

CL(L/h) 16.8 13.8

AUCss (mg*h/L) 30.8 23.4

T1/2 (h) 4.2-8.5


ProceedStudy•StudyDesign:• Phase3,multicenter,stratified,randomized,double-blindtrialtoevaluateIVdelafloxacinvsvancomycin/aztreonamforABSSSI

•Intervention:• Delafloxacin300mgIVorvancomycin15mg/kg(actualbodyweight)withaztreonam2gq12h• Aztreonamdiscontinuedifculturesdidnothavegramnegativeorganisms

• Duration:5-14days• Excludeddiabeticfootinfections

•Outcomes:• Primary:48-72hr(±2)responseof≥20%reductioninerythemaoflesionwithoutevidenceofclinicalfailure

• Secondary:• Investigatorassessedsuccessatfollowupvisit

JAntimicrob Chemother.2017;72:3471-3480

Proceed- ResultsDelafloxacin Vancomycin/

AztreonamPercentagedifference(95%CI)

48-72hr objectiveresponse 78.2% 80.9% -2.6(-8.78,3.57)

Cureatfollow-up 52% 50.5% 1.5(-6.11,9.11)

Successatfollow-up 81.6% 83.3% -1.7(07.55,4.13)

Microbiologicresponse 97.8% 98.4% Notprovided

MRSACureatlast followup 83.6% 72.7% 10.9(-3.71,25.11)

Cureinobesepatientsatlastfollowup

71.7% 57.4% 14.2(1.34, 26.9)


Proceed– ResultsAdditionalComments•Baselinedemographicssimilarbetweenthegroups

•Staphylococcusaureusidentifiedin65.4%and66.8%ofpatientswithpositiveculturesinthedelafloxacinandvancomycin/aztreonamarmsrespectively

•NocasesofClostridiumdifficileoccurred,onepatienthadanincidenceofhypoglycemia,twopatientshadhyperglycemia

•Rateoftargetattainmentwithvancomycinwasnotprovided

•Only2patientsinthedelafloxacinand5patientsinthevancomycin/aztreonamgrouphadPseudomonasaeruginosa


PotentialNiche?•Additionaltrialsonclinicaltrials.gov• Delafloxacinvs.moxifloxacin forCABPrecruiting• DelafloxacinvsceftriaxoneforuncomplicatedGonorrhea- terminated

•Clinicalthoughts• Potentiallyinobesepatientswhereagrampositiveorganismisidentified• Therearerumorsthatitcouldbeusedforpolymicrobial infectionslikediabeticfootulcersbutthereisnotliteraturetosupportityet

• Concernforresistancedevelopmentduringtreatment• Interestingthatitdoesn’thaveaneffectonQTc– potentialtreatmentopportunities

• Cheaperthanvancomycin/aztreonamforpatientswithbetalactamallergy• NoCDI

Ozenoxacin(Xepi™)•Indication:topicaltreatmentofimpetigoduetoStaphylococcusaureusorStreptococcuspyogenes inpatients>2monthsofage

•Mechanismofaction:inhibitstopoisomeraseIIandIV

•Dose:• Applyathinlayertotheaffectedareatwicedailyfor5days• Eachgramcontains10mgofozenoxacin1%

•Warnings• Bacterialovergrowth

•Negligibletonosystemicabsorption

•AntagonisticrelationshipbetweenciprofloxacinandozenoxacinforStaphylococcusaureus

Xepi™.[PackageInsert].Fairfield,NJ:Medimetriks Pharmaceuticals;2017

OzenoxacinClinicalTrial•StudyDesign:• Multicenter,randomized,placebo-controlled,parallel,blinded,superiorityphase3studytoozenoxacin,retapamulin,andplacebofornonbullous orbullousimpetigo

•Intervention:• Ozenoxacin1%creamvsplacebocreamappliedtwicedaily• Retapamulin 1%ointmentvsplaceboappliedtwicedaily• Duration:5days

•Outcomes:• Primary:clinicalresponseatendoftherapy(visit3,day6-7)• Secondary:• Clinicalresponseinnon-ITTpopulations• Clinicalresponseatday3-4(visit2)andday10-13(visit4)• Sizeofaffectedareaatvisits2,3,and4• Microbiologicresponse• Timetoclinicalresponse

FutureMicrobiology.2014;9(9):1013-23

Ozenoxacin- Results•Demographicsweresimilar

Ozenoxacin(n=155)

Placebo(n=156)

P-value Retapamulin(n=154)

Placebo(n=156)

P-value

Clinicalsuccessatvisit3

54(34.8%) 30(19.2%) 0.003 58(37.7%) 30(19.2%) 0.189

Microsuccessatvisit3

122(79.2%) 86(56.6%) P<0.0001

125(81.7%) 86(56.6%) P<0.001

FutureMicrobiology.2014;9(9):1013-23

Phase3Pipeline

Iclaprim•Syntheticdiaminopyrimidine

•Mechanismofaction:selectivelyinhibitsdihydrofolate reductase(DHFR)

•Spectrumofactivity:similartotrimethoprim• Grampositive• Staphylococcusaureus (MSSAandMRSA)• Coagulasenegativestaphylococci• Variousstreptococcalspecies• Enterococcus

• Gramnegative• Neisseriagonorrheae,Haemophilusinfluenza,Moraxellacatarrhalis,Enterobacteriaceae

• Atypical• Chlamydiatrachomatis,Chlamydiapneumoniae,Mycoplasmaspecies,Legionellapneumophila

AnnPharmacother 2009;43:1107-14

Revive-1•StudyDesign:• Phase3,multicenter,double-blind,randomizedtrialcomparingiclaprim withvancomycinforABSSSIduetogrampositiveorganisms

•Intervention:• Iclaprim80mgIV(500mLNS)over120minutesq12h• Vancomycin15mg/kgIVover120minutesq12h(troughlevelsatdose5)• Duration:5-14days• ExcludedpatientswithdiabeticfootulcersanduncomplicatedSSTI

•Outcomes:• Primary:comparetheearlyclinicalresponseat48-72hrs• Secondary:• Clinicalcurerateattestofcure• Safetyandtolerability

Huang.Clin InfectDis.2017:XX(00):1-8

Revive-1- Results•Baselinecharacteristicsweresimilarexcept• Afewmoresevereinfectionsandwoundinfections• Atadlessmajorcutaneousabscess(13.4%vs18.3%)• FewerpatientswithdiabetesandrenalimpairmentbutmoreIVdrugusers

Huang.Clin InfectDis.2017:XX(00):1-8

Iclaprim– Potentialniche?•Otherclinicaltrialsonclinicaltrials.gov• IclaprimvsvancomycinforABSSSI– Revive-2:completed• IclaprimvsvancomycinforHAP,VAP,orHCAP:terminated• IclaprimvslinezolidincSSTI-Assist-1:completed• IclaprimvslinezolidincSSTI-Assist-2:completed

•Thoughts• Noinformationonvancomycintargetattainment• Whywasthepneumoniastudywascanceled?• Goodoptionforcomplicatedvancomycindosing• UnclearclinicalutilityotherthanforMRSA

Lefamulin•Pleuromutilin

•Mechanismofaction:bindstothe23softhe50ssubunitatthepeptidyltransferasecenterinhibitingpeptidebondformationandinhibitingproteinsynthesis• https://www.youtube.com/watch?v=gFG8yWYV3ew

HTTPS://WWW.NABRIVA.COM/PIPELINE-RESEARCHCOLDSPRINGHARB PERSPECT MED2017;7:A027110SCI REP2016;6:39004

GramPositive GramNegative Atypicals Anaerobes

Staphylococcalaureus(MSSA,MRSA,VRSA)

Haemophilussp. Mycoplasmapneumoniae

Propionibacteriumacnes

Coagulase negativeStaphylococcusaureus

Moraxella catarrhalis Chlamydiapneumoniae

Peptocstreptococcus sp

Streptococcuspneumoniae

Neisseria sp. Legionellapneumophilia

Prevotella sp

Enterococcus faecium(VRE)

Clostridiumperfringens

LefamulinClinicalTrial•Studydesign:double-blind,parallelgroup,multicenterphase2studyforuseoflefamulin inABSSSI

•Interventions:• Lefamulin100mgIVq12h• Lefamulin150mgIVq12h• Vancomycin1g(adjustedtoinstitutionguidelines)IVq12h• Duration:5-14days

•Outcomes:• Primary:clinicalsuccessattestofcure• Secondary:• Microbiologicaloutcome• Safety

Antimicrob AgentsChemother.2013;57(5):2087-2094

Lefamulin•Baselinecharacteristicsweresimilarexcept:• Vancomycingrouphadslightlyfewerpatientswithfever(n=3vs5and7)• Lefamulin100mghadmorepatientswithalowerextremityinfectionwhilevancomycinhadmorepatientswithupperextremityinfections

• Lefamulin150mghadmorepatientswithdiabetesmellitusandhigherweight

•Micro:• 151/155patientshadagrampositiveinfection• 90.8%withStaphylococcusaureuswith69.1%beingMRSA

#ofPatients Success Failure 95%CI

Lefamulin 100mg 60 54(90) 6(10) 79.5,96.2

Lefamulin150mg 54 48(88.9) 11.1) 77.4,95.8

Vancomycin1g 51 47(92.2) 4(7.8) 81.1,97.8

Antimicrob AgentsChemother.2013;57(5):2087-2094

Potentialniche?•Othertrialsonclincialtrials.gov• Lefamulinvsmoxifloxacin forCAP– completed• Lefamulinvsmoxifloxacin w/orwo/linezolidforCAP–completed

•ManufacturerwebsitementionspossibleuseforABSSSI,STIs,VABP,HABP,OM,andPJI

•Thoughts:• Noinformationonvancomycintargetattainment• Excitedforthisnewmechanismofaction• GreatdrugforCAPgivenspectrumofactivityandhighbarriertoresistance

• CouldbegoodforAspirationpneumonia,STIs,MRSAinfections,obesity

• DoesnotcoverEnterobacteriaceae,B.fragilis,or E.faecalis socansparegutflora– CDIimplications?

Cefiderocol

Yamano ECCMIDpresentation2017

Cefiderocol•Spectrumofactivity• Noactivityagainstgrampositiveorganisms• CoversgramnegativebacteriaincludingCREsandMDRnon-fermenters• Stabletoserine(KPC,OXA,etc.)andmetalloβ-lactamases(VIM,IMP,NDM,L1,etc.)• PotentactivityagainstAcinetobacterbaumannii,Pseudomonasaeruginosa,Escherichiacoli,

Klebsiellapneumoniae,Stentotrophomonasmaltophilia

• MICtestingshouldbedoneinirondepletedmedium

•Clinicaltrialsonclinicaltrials.gov• cUTIvsimipenem/cilastatin – completed• SevereinfectioncausedbyCREvsbestavailabletherapy– recruiting• Nosocomialpneumoniacausedbygramnegativepathogensvsmeropenemandlinezolid- recruiting

Yamano ECCMIDpresentation2017

CefiderocolClinicalTrials•StudyDesign:• Phase3,multicenter,double-blind,randomized,non-inferioritytrialtoevaluatecefiderocolfortreatmentofcUTIw/orw/opyelonephritis

•Intervention:• Cefiderocol2gIVtid• Imipenem/cilastatin 2gIVtid• Duration:7-14days• Excludeddiabeticfootinfections

•Outcomes:• Primary:compositeclinicalandmicrobiologicalresponseatTOCinMITTpopulation

• Secondary:• MicrobiologicalresponseatTOCinMITTpopulation

PortsmouthECCMIDpresentation2017

Cefiderocol- Results•Baselinedemographicsweresimilarexcept• ThecefiderocolgrouphadafewmorecUTIw/orw/opyelonephritis(74.2%vs70.6%)

• Thecefiderocolgrouphadefeweracuteuncomplicatedpyelonephritis(25.8%vs29.8%)

• Thecefiderocolgrouphadafewmorepatientswithahistoryofneoplasmsandchronicpyelonephritis

•Adverseeffects• Similarbutnumericallymorefortheimipenem/cilastatin arm• Themostcommonsideeffectsinthecefiderocolarmwere• Diarrhea(4.3%)• Hypertension(4.3%)• Constipation(3.3%)• Infusionsitepain(3%)


Cefiderocol– MicroResults

60.30% 19.00%

7.10%

6.70% 3.60% 3.30% Cefiderocol(n=252)

E.coli K.pneumoniae

P.aeruginosa P.mirabilis

E.cloacae Other

66.40%

21.00%

4.20% 1.70%

0.80% 5.90% Imipenem/cilastatin(n=119)

E.coli K.pneumoniae

P.aeruginosa P.mirabilis

E.cloacae Other


Cefiderocol– Primaryoutcome


Cefiderocol– PotentialNiche?•Novelmechanismofaction

•Strictlygramnegativeagentwithgoodstabilitytoβ-lactamases• MDROs• EmpiricforriskfactorsforMDROs?• Neutropenicfever?

•CoverageagainstS.maltophiliacouldbeapotentialniche

•I’mcuriouswhytheychoseimipenemastheircomparator

•Concernforimpactonpatient’sironlevelsandmicrobiologicaltesting

Imipenem/cilastatin/relebactam•Bicyclicdiazabicyclooctane β-lactamaseinhibitoragainstclassAandclassCβ-lactamases

•Mechanismofaction:• Imipenem – bindstoPBPtoinhibitcellwallsynthesis• Cilastatin– competitiveinhibitionofdehydropeptidase ofrenaltubulestopreventimipenemmetabolism

• Relebactam– β- lactamaseinhibitor• ActiveagainstclassAandCβ- lactamases• PK/PDparameter:AUC:MIC

•QualifiedInfectiousDiseaseProductforHABP,VABP,cIAI,andcUTI

HTTP://INVESTORS.MERCK.COM/NEWS/PRESS-RELEASE-DETAILS/ANTIMICROB AGENTSCHEMOTHER 2017.24:61(6).PII:E02209-16

Imipenem/cilastatin ReviewGramPositiveAerobicBacteria GramNegative AerobicBacteria

Enterococcus faecalis Acinetobacter sp.

Staphylococcus aureus Citrobactersp.

Staphylococcus epidermidis Enterobactersp.

Streptococcusagalactiae Escherichiacoli

Streptococcuspneumoniae Gardnerella vaginalis

Streptococcus pyogenes Haemophilusinfluenza

Klebsiellasp.

Morganellamorganii

Proteusvulgaris

Providencia rettgeri

Pseudomonasaeruginosa

Serratiasp.Primaxin™.[PackageInsert].WhitehouseStation,NJ:Merck &Co.2017

Imipenem/cilastatin/relebactamClinicalTrialforcUTI•StudyDesign:• Prospective,randomized,double-blind,multicenter,non-inferiority(withnestedsuperiority),Phase2bdose-rangingstudytoevaluatetwodoseofimipenem/cilastatin/relebactam vsimipenem/cilastatin forcUTI

•Intervention:• Imipenem/cilastatin 500mgIV+relebactam250mgIVover30minq6h• Imipenem/cilastatin 500mgIV+relebactam125mgIVover30minq6h• Imipenem/cilastatin 500mgIV+placeboIVover30minq6h• Ifadequateresponseat96hrscouldswitchtooralciprofloxacin

•Outcomes:• Primary:MicrobiologicalresponseatdiscontinuationofIVtherapy• Secondary• Microbiologicalresponseatearlyfollowupandlatefollowup• MicrobiologicalresponseatdiscontinuationofIVtherapyinimipenem-resistantpathogens• ClinicalresponseatdiscontinuationofIVtherapy,earlyfollowup,andlatefollowup

JAntimicrob Chemoth.2017:72:2616-2626

Imipenem/cilastatin/relebactamResults•Baselinedemographicssimilarexcept• 250mgrelebactamgrouphadslightlyfewernephrolithiasis• 250mgrelebactamgrouphadslightlyfewerpatientswithK.pneumoniae• Placebogrouphadslightlymorepatientswithresidualurine• Placebogrouphadfewerimipenemnon-susceptiblepathogens


Imipenem/cilastatin/relebactamMicro


Imipenem/cilastatin/relebactamResults


Imipenem/cilastatin/relebactamClinicalTrialscIAI•StudyDesign:• Prospective,randomized,double-blind,multicenter,Phase2dose-rangingstudytoevaluatetwodoseofimipenem/cilastatin/relebactam vsimipenem/cilastatin forcIAI

•Intervention:• Imipenem/cilastatin +relebactam250mgIVover30minq6h• Imipenem/cilastatin +relebactam125mgIVover30minq6h• Imipenem/cilastatin +placeboIVover30minq6h• Duration4-14days

•Outcomes:• Primary:favorableclinicalresponseatdiscontinuationofIVtherapy

Antimicrob AgentsChemother.2016:60:6234-6243

Imipenem/cilastatin/relebactamResults•Baselinedemographicsweresimilarexcept• Theplacebogrouphadfewerpreoperativeandmorepostoperativeenrollmenttimes

• APACHE2scoresweresimilarwithmostbeing≤15

•Mostcommondiagnoses:• Complicatedappendicitis(52.5%)• Complicatedcholecystitis (16.5%)• Perforatedhollowviscus(11.4%)

•Allcomparisonsofproportionofsubjectswithfavorableclinicalresponsewerenon-statisticallysignificant


Imipenem/cilastatin/relebactamMicro


Potentialniche?•Trialsonclinicaltrials.gov:• Imipenem/cilastatin/relebactam inJapanesepatientswithcIAI orcUTI–recruiting

• Imipenem/cilastatin/relebactamvscolistimethate +imipenem/cilastatin forimipenemresistantbacteria– completed

• PKinpediatricstudy– recruiting• Imipenem/cilastatin/relebactam vspiperacillin/tazobactam forbacterialpneumonia– recruiting

•Thoughts:• LastlinetherapymostlyforMDRPseudomonasaeruginosawithsusceptibilityresults

• Stillworriedaboutsideeffectsofimipenem• Likelydosewillbeimipenem/cilastatin 500mg+relebactam250mgIVq6h

Wheredoesrelebactamfitin?ESBLproducer Amp-C

producerCarbapenamase

Ampicillin-sulbactam R R R

Piperacillin-tazobactam V R R

Ceftazidime-avibactam S S V

Ceftolozane-tazobactam S S V

Aztreonam-avibactam S S V

Meropenem-vaborbactam V S V

Imipenem/cilastatin-relebactam

V S V

MayoClin Proc 2015;90(3):395-403UnpublishedinformationrequestfromTheMedicinesCompanyAntimicrob AgentsChemother.2017;61:e02209-16

R=resistantS=sensitiveV=variable

Questions?

NewBugs?NewDrugs!CRYSTAL HOWELL , PHARMD, BCPS

UNIVERS ITY OF NORTHTEXAS HEALTHSC IENCE CENTER

MEDICAL C ITY DALLAS

CRYSTAL .HOWELL@UNTHSC .EDU

New Bugs? New Drugs! - MSHP Homemshptx.org/uploads/3/4/1/8/34180063/crystal_howell_-_final.pdf ·...

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Transcript of New Bugs? New Drugs! - MSHP Homemshptx.org/uploads/3/4/1/8/34180063/crystal_howell_-_final.pdf ·...