OverviewofNewerGramͲ NegativeAntimicrobialAgents AnjlyKunapuli,PharmD OklahomaStateUniversityMedicalCenter October27,2017

Objective

• Explaintheroleofceftazidime/avibactam,ceftolozane/tazobactam andmeropenem/vaborbactaminthemanagementofresistantGramͲ negativeinfections TopAntibioticResistanceThreats UrgentThreats SeriousThreats C.difficile MultidrugͲresistantAcinetobacter CarbapenemͲresistantEnterobacteriaceae DrugͲresistantCampylobacter DrugͲresistantN.gonorrhoeae FluconazoleͲresistantCandida ESBLproducingEnterobacteriaceae ConcerningThreats VancomycinͲresistantEnterococcus VRSA MultidrugͲresistantP.aeruginosa ErythromycinͲresistantGroupA DrugͲresistantNonͲtyphoidalSalmonella Streptococcus DrugͲresistantS.typhi ClindamycinͲresistantGroupB DrugͲresistantShigella Streptococcus MRSA DrugͲresistantS.pneumoniae DrugͲresistanttuberculosis

CDC.[AccessedOctober1,2017]AntibioticResistanceThreatsintheUnitedStates,2013. https://www.cdc.gov/drugresistance/pdf/arͲthreatsͲ2013Ͳ508.pdf

AntibioticPipeline

Antibiotic Agents Approved for Use in the United States 18

16

14

12

10

8

6

4

2

0 1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 2013-2016 Total # New Antibiotic Agents Approved PushingAntimicrobialR&DForward

• 10x20Initiative • Multidisciplinarycollaborationtodevelopcreativeincentivesthatwill stimulatenewantibacterialresearchanddevelopment • CreateasustainableglobalantibacterialdrugR&Denterprisetodevelop10 new,safe,andeffectiveantibioticsby2020

• GeneratingAntibioticsIncentivesNowAct • QualifiedInfectiousDiseaseProduct(QIDP) • AntibacterialorantifungaldrugsintendedtotreatseriousorlifeͲthreateninginfections • FDA:Priorityreviewstatusandexpeditedregulatoryapprovalprocess • Qualifiesthedrugsforfiveadditionalyearsofmarketingexclusivity

ClinInfectDis.2015April;50(8):1081–1083.

RecentlyApprovedAntimicrobialAgentsintheUS

Number Drug Year 1 Ceftaroline 2010 2 Dalbavancin 2014 3 Tedizolid 2014 4 Oritavancin 2014 5 Ceftolozane/Tazobactam 2014 6 Ceftazidime/Avibactam 2015 7 Meropenem/Vaborbactam 2017 8 Delafloxacin 2017 NewerGramͲNegativeAgents

• Ceftazidime/avibactam(Avycaz®)

• Ceftolozane/tazobactam(Zerbaxa®)

• Meropenem/vaborbactam(Vabomere®)

PreͲAssessment

1. Whichofthefollowingagentsiseffectiveintreatinginfections causedbyKlebsiellapneumoniaecarbapemenase(KPC)Ͳ producing Enterobacteriaceae? a.Ceftazidime/avibactam(Avycaz®) b.Meropenem/vaborbactam(Vabomere®) c.Ceftolozane/tazobactam(Zerbaxa®) d.aandb e.aandc ClassificationofEnzymes

AmblerClass A B C D ActiveSite Serine Metallo Serine Serine Enzyme TEM,SHV,CTXͲM, NDM,IMP,VIM AmpC OXA KPC Organism Enterobacteriaceae, Enterobacteriaceae, Enterobacterspp, Enterobacteriaceae, Pseudomonas Pseudomonas Citrobacterspp Acinetobacter Acinetobacter Pseudomonas Pseudomonas Substrate Ampicillin, penicillins,1stͲ BroadͲspectrum Cephamycins,3rd cloxacillin,1stͲ4th 4th generation including generation generation cephalosporins, carbapenems cephalosporins cephalosporins, monobactams carbapenems BroadͲspectrum including Except: carbapenems monobactams

ClinInfectDis.2016Jul;63:234Ͳ241.

Ceftazidime/Avibactam Ceftolozane/Tazobactam MechanismofAction

• Ceftazidime • Ceftolozane • Inhibitscellwallsynthesis • Inhibitscellwallsynthesis • Avibactam • Similarstructuretoceftazidimebutwith enhancedgramͲnegativeactivity • BetaͲlactamaseinhibitor • Improvedoutermembranepermeability • љavailabilityofacƟveenzymesfor andstabilityagainstsomeAmpCbetaͲ hydrolysis lactamases(P.aeruginosa) • BindscovalentlyandreversiblytoɴͲ lactamasesandallowsavibactam • Tazobactam recyclizationtoinactivateanotherɴͲ • BetaͲlactamaseinhibitor lactamase • BindsirreversiblytoɴͲlactamases

Pharmacother.2015Aug;35(8):755Ͳ770.

ClassificationofEnzymes

AmblerClass A B C D ActiveSite Serine Metallo Serine Serine Enzyme TEM,SHV,CTXͲM, NDM,IMP,VIM AmpC OXA KPC Organism Enterobacteriaceae, Enterobacteriaceae, Enterobacterspp, Enterobacteriaceae, Pseudomonas Pseudomonas Citrobacterspp Acinetobacter Acinetobacter Pseudomonas Pseudomonas Substrate Ampicillin, penicillins,1stͲ4th BroadͲspectrum including Cephamycins,3rd cloxacillin,1stͲ4th generationcephalosporins, carbapenems generationcephalosporins generation monobactams cephalosporins, Except:monobactams carbapenems BroadͲspectrum including carbapenems

Inhibitedby Yes No Yes Yes(OXAͲ48) Avibactam Inhibitedby Yes No No No Tazobactam No

ClinInfectDis.2016Jul;63:234Ͳ241. Microbiology

Ceftazidime/Avibactam Ceftolozane/Tazobactam • GramͲnegativeactivity • GramͲnegativeactivity • Enterobacteriaceae • Enterobacteriaceae • Carbapenemresistant(KPC) • P.aeruginosa • P.aeruginosa • NoAcinetobacter,Stenotrophomonas • NoAcinetobacter,Stenotrophomonas • GramͲpositiveactivity • GramͲpositiveactivity • SomeStreptococcalspp. • SomeStreptococcusspp. • LimitedStaphylococcusspp. • LimitedStaphylococcusspp. • NoEnterococcusspp. • NoEnterococcusspp. • Anaerobicactivity • Anaerobicactivity • Propionibacteriumspp • Propionibacteriumspp • Bacteroidesspplesspredictable • NoBacteroidesspp • NoClostridiumspp • NoClostridiumspp

ClinInfectDis.2016Jul;63:234Ͳ241.

Meropenem/Vaborbactam MechanismofAction

• Firstcombinationbasedcarbapenem • Meropenem • Bactericidal,inhibitscellwallsynthesis • StabletohydrolysisbymostbetaͲlactamases • Exception:carbapenemhydrolyzingbetaͲlactamases • Vaborbactam • NovelbetaͲlactamaseinhibitor

ClassificationofEnzymes

AmblerClass A B C D ActiveSite Serine Metallo Serine Serine Enzyme TEM,SHV,CTXͲM, NDM,IMP,VIM AmpC OXA KPC Organism Enterobacteriaceae, Enterobacteriaceae, Enterobacterspp, Enterobacteriaceae, Pseudomonas Pseudomonas Citrobacterspp Acinetobacter Acinetobacter Pseudomonas Pseudomonas Substrate Ampicillin, penicillins,1stͲ4th BroadͲspectrum including Cephamycins,3rd cloxacillin,1stͲ4th generationcephalosporins, carbapenems generationcephalosporins generation monobactams cephalosporins, Except:monobactams carbapenems BroadͲspectrum including carbapenems

Inhibitedby Yes No Yes Yes(OXAͲ48) Avibactam Inhibitedby Yes No No No Tazobactam No Inhibitedby Yes No Yes No Vaborbactam

ClinInfectDis.2016Jul;63:234Ͳ241. Microbiology

• Meropenem • BroadͲspectrumgramͲnegativecoverage • MultiͲdrugresistantorganisms:Acinetobacter,Enterobacteriaceae,P.aeruginosa • GramͲpositive • Streptococcusspp. • MethicillinͲsensitiveStaphylococcusspp. • Some Enterococcusspp.(NoVRE) • Vaborbactam • Extendsspectrumofmeropenemtoinclude:carbapenemͲresistant Enterobacteriaceae • DoesnotexpandcoveragetocarbapenemͲresistant Acinetobacterspp., P. aeruginosa or S.maltophilia

FDAApprovedIndications

Ceftazidime/avibactam Ceftolozane/tazobactam Meropenem/vaborbactam FDAApproved 1.ComplicatedintraͲabdominal 1.ComplicatedintraͲabdominal 1.Complicatedurinarytract infections(with metronidazole) infections(with metronidazole) infections, including 2.Complicatedurinarytract 2.Complicatedurinarytract pyelonephritis infections, including infections, including pyelonephritis pyelonephritis

OnͲGoing Trials 1.HospitalͲAcquired 1.HospitalͲAcquired 1.HospitalͲAcquired Pneumonia Pneumonia Pneumonia 2.VentilatorͲAssociated 2.VentilatorͲAssociated 2.VentilatorͲAssociated Pneumonia Pneumonia Pneumonia 3.Pediatrics 3.Pediatrics OnͲGoing Trials Cysticfibrosis Cysticfibrosis Pediatrics Pharmacokinetics Burn Diabetic footinfections

www.clinicaltrials.gov Summary

• NonewcompoundsactiveagainstGramͲnegativeorganismshavebeenapprovedin recentyears

• Ceftazidime/avibactam,ceftolozane/tazobactamandmeropenem/vaborbactamofferan alternativetoagentswithhightoxicity:polymyxinsandaminoglycosidesforthe treatmentofresistantGramͲnegativeorganisms

• CeftazidimeͲavibactamandmeropenem/vaborbactamaretheonlybetaͲlactam/betaͲ lactamaseinhibitorcombinationagentstodemonstrateactivityagainstKPCs

• Ceftolozane/tazobactamhaspotentactivityagainst P.aeruginosa duetoitsabilityto evademanyresistancemechanismsbutlacksactivityagainstKPCproducingorganisms

• Theuseoftheseagentsshouldbereservedforpatientsforthetreatmentofresistant GramͲnegativeinfectionswherenootherreasonablealternativesexist

PostͲAssessment

1. Whichofthefollowingagentsiseffectiveintreatinginfections causedbyKlebsiellapneumoniaecarbapenemase(KPC)Ͳ producing Enterobacteriaceae? a.Ceftazidime/avibactam(Avycaz®) b.Meropenem/vaborbactam(Vabomere®) c.Ceftolozane/tazobactam(Zerbaxa®) d.aandb e.aandc AdditionalReading

1.ZasowskiEJ,RybakJM,RybakMJ.TheBetaͲLactamsStrikeBack: CeftazidimeͲAvibactam.Pharmacotherapy.2015Aug;35(8):755Ͳ770. 2.ChoJC,FiorenzaMA,EstradaSJ.Ceftolozane/Tazobactam:ANovel Cephalosporin/BetaͲLactamaseInhibitorCombination. Pharmacotherapy.2015;35(7):701Ͳ715. 3.VanDuinD,Bonomo RA.Ceftazidime/Avibactamand Ceftolozane/Tazobactam:SecondͲgenerationɴͲLactam/ɴͲLactamase InhibitorCombinations.Clin InfectDis.2016;63(2):234–41.