AnnLloyd,PharmD,BCPSͲAQID AssistantProfessor TheUniversityofOklahomaCollegeofPharmacy ClinicalPharmacySpecialistinInfectiousDiseases SaintFrancisHospital Tulsa,OK OSHPFallMeeting October23,2015

Discusstherecentlyapprovedtreatmentsfor GramͲpositiveandGramͲnegativeorganisms Describetheimpactofthenewdrugapprovals onthetreatmentofrelevantmultidrugresistant organisms Formulatetherapeuticregimensforthe treatmentofmultidrugresistantorganisms

Slowtheemergenceof resistantbacteriaandprevent spreadofresistant Establishstewardship programsinallhospitalsand improvestewardshipacross allhealthcaresettings Reduceinappropriateuseby 50%inoutpatientand20%in inpatientsettings Establishstate resistanceprevention programs Eliminatetheuseof medicallyͲimportant forgrowth promotioninfoodͲproducing animals https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_co mbating_antiboticͲresistant_bacteria.pdf Threat Level Pathogen Urgent difficile CarbapenemͲresistantEnterobacteriaceae Neisseriagonorrhoeae

Serious MultidrugͲresistant Acinetobacter DrugͲresistant Campylobacter FluconazoleͲresistantCandida Extended SpectrumɴͲLactamaseProducing Enterobacteriaceae MultidrugͲresistant Pseudomonasaeruginosa DrugͲresistant SalmonellaandSalmonellatyphi DrugͲresistant Shigella MethicillinͲresistantStaphylococcusaureus(MRSA) DrugͲresistantpneumoniae DrugͲresistant Tuberculosis

https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_co mbating_antiboticͲresistant_bacteria.pdf

Enterococcusfaecium Staphylococcusaureus Klebsiellapneumoniae Acinetobacterbaumannii Pseudomonasaeruginosa Enterobacterspp.

Sulfonamides Tetracyclines

BetaͲlactams Glycopeptides

Aminoglycosides Quinolones

Macrolides Oxazolidinones Drug ApprovalYear 2009 Ceftaroline 2010 May2014 Tedizolid June2014 August2014 Ceftolozane/ December 2014 / February2014

IDSA.ClinInfectDis.2010;50(8):1081Ͳ1083. BoucherHW,etal.ClinInfectDis.2013;56(12):1685Ͳ169 GSisa58ͲyearͲoldwomanwhoisadmitted fromarehabilitationfacilityfollowingafever. Shehasahistoryofafallthatresultedinspinal cordinjury6weeksago.Urinalysisshows50 WBCs,positivefornitritesandleukocyte esterase.ShewastreatedforanE.coli urinary tract(UTI)duringherprevious hospitalization.Thephysiciancallsthe pharmacyforarecommendationfortreatment ofapresumedUTI.

CarbapenemͲresistantEnterobacteriaceae 9,000infectionsperyear 600deaths Acinetobacterspp. 12,000infectionsperyear 500deaths ExtendedͲspectrumbetaͲlactamases 140,000infectionsperyear 1700deaths DrugͲresistantPseudomonasaeruginosa 6,700infectionsperyear 440deaths http://www.cdc.gov/drugresistance/biggest_threats.html

Ceftazidime Ceftazidime/avibactam Amikacin Gentamicin Ceftolozane/tazobactam Tobramycin /tazobactam Tigecycline Ciprofloxacin Levofloxacin /cilastatin Brandname:Zerbaxa™ Pharmacologicclass:fifthgeneration Approvaldate:December19,2014 Manufacturer:Merck Indication:complicatedintraͲabdominal infections(incombinationwith), urinarytractinfectionsincludingpyelonephritis Dose:1.5gramsevery8hours

Mechanism Bactericidal Inhibitscellwallsynthesisthroughbindingof penicillinͲbindingproteins(PBP) Pharmacokinetics 2:1ratio(ceftolozane:tazobactam) HalfͲlife:2.3hours Modestproteinbinding Primarilyrenalelimination

ChoJC.Pharmacotherapy. 2015;35(7):701Ͳ715.

CrCl (mL/min) Dosage Adjustment Greaterthan50 1.5gramsIVq8h 30Ͳ50 750mgIVq8h 15Ͳ29 375 mgIVq8h EndͲstage renaldisease(ESRD)on 750 mgIVx1followedby150mgIVq8h hemodialysis(HD) OnHDdays,givedosefollowingdialysis

Zerbaxa™[packageinsert].WhitehouseStation,NJ:Merck&CO,Inc.2014. Nosignificantinteractions

Hypersensitivityreactions Nausea Diarrhea Headache Pyrexia

Zerbaxa™[packageinsert].WhitehouseStation,NJ:Merck&CO,Inc.2014.

Posted5/20/2015 Doseconfusionand errors Doseshouldbe1.5grams

http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalp roducts/ucm447629.htm P.aeruginosa (includingdrugͲresistantstrains) Enterobacteriaceae (includingsomeESBLͲ producingstrains) Streptococcus(S.anginosis,S.constellatus,S. salivarius) LimitedStaphylococcusspp.Activity LacksactivityagainstmetalloͲɴͲlactamasesand carbapenemase Bacteroides(fragilis >>>otherspecies)

ChoJC.Pharmacotherapy. 2015;35(7):701Ͳ715.

Study Design PrimaryOutcome Results ComplicatedIntraͲ Prospective,doubleͲ Clinicalresponseat 83% in abdominalinfections blind, randomized, testofcurevisit ceftolozane/tazobactam multiͲcentertrial armvs.87.3%inthe meropenemarmmetthe Ceftolozane/tazobactam primaryoutcome +metronidazolevs. meropenem

N=993 ASPECTͲcUTI DoubleͲblind, Composite of 76.9% of randomized,nonͲ microbiological ceftolozane/tazobactam inferiority trial eradicationand patientsvs.68.4%of clinicalcureatthe levofloxacinpatientsmet CeftolozaneͲtazobactam testofcurevisit theprimaryoutcome vs.levofloxacin

ChoJC.Pharmacotherapy. 2015;35(7):701Ͳ715.

PharmacokineticsandsafetyinadultCF patients Safetyandefficacyinnosocomialpneumonia Pediatricpatients

https://clinicaltrials.gov Brandname:Avycaz™ Pharmacologicclass:thirdgeneration cephalosporin Approvaldate:February25,2015 Manufacturer:Actavis Indication:ComplicatedintraͲabdominal infections(incombinationwithmetronidazole), complicatedurinaryͲtractinfections(including pyelonephritis) Dose:2.5gramsIVevery8hourseachdose infusedover2hours

Mechanism Bactericidaleffect BindingtoPBPandinhibitionofcellwallsynthesis Pharmacokinetics HalfͲlife:2.7hours Predominantlyrenallyeliminated Lowproteinbinding

ZasowskiEJ,etal.Pharmacotherapy.2015;35(8):755Ͳ770.

EstimatedCreatinineClearance (mL/min) Dosage Adjustment 31Ͳ50 1.25gramsIVevery8hours 16Ͳ30 0.94gramsIVevery12hours 6Ͳ16 0.94gramsIvevery24hours Lessthanorequalto50.94gramsIVevery48hours;administer afterHDonHDdays

DecreasedefficacyinpatientswithCrCl30Ͳ50mL/min

Avycaz™[packageinsert].Cincinnati,OH:ForestPharmaceuticals,Inc.2015. Probenecid

Hypersensitivity CNSreactions Nausea Vomiting Diarrhea Abdominalpain Headache Dizziness

ZasowskiEJ,etal.Pharmacotherapy.2015;35(8):755Ͳ770. Avycaz™[packageinsert].Cincinnati,OH:ForestPharmaceuticals,Inc.2015.

Posted9/22/15 Warningrelatedtodose confusionandmedication errors Doseshouldbeasumof theproducts(2.5grams)

http://www.fda.gov/safety/medwatch/safetyinforma tion/safetyalertsforhumanmedicalproducts/ucm463 595.htm Enterobacteriaceae (includingsomeESBLsand carbapenemaseproducingstrains) Pseudomonasaeruginosa Limitedanaerobicactivity LimitedGramͲpositiveactivity(similarto ceftazidime)

Study Design Primary Results Outcome IntraͲabdominal Prospective, multicenter, Clinicalresponseat 91.2%of randomized,doubleͲ testͲofͲcurevisit ceftazidime/avibactam blind patients and93.4%of meropenempatientsmet Ceftazidime/avibactam+ theprimaryoutcome metronidazolevs. meropenem

N=204 Complicated UTI Prospective, multicenter, Microbiologic 70.4% of randomized,doubleͲ responseattestͲofͲ ceftazidime/avibactam blind cure visit patientsand71.4%of imipenempatientsmetthe Ceftazidime/avibactam primaryoutcome vs.imipenem

N=137

ZasowskiEJ,etal.Pharmacotherapy.2015;35(8):755Ͳ770.

Pharmacokineticsincysticfibrosis Comparedtomeropeneminadultshospitalized withnosocomialpneumonia Childrenage3monthsͲ18yearswith complicatedintraͲabdominalinfections Childrenage3monthsͲ18yearswith complicatedurinarytractinfections

https://clinicaltrials.gov GSisa58ͲyearͲoldwomanwhoisadmitted fromarehabilitationfacilityfollowingafever. Shehasahistoryofafallthatresultedinspinal cordinjury6weeksago.Urinalysisshows50 WBCs,positivefornitritesandleukocyte esterase.ShewastreatedforanE.coli urinary tractinfection(UTI)duringherprevious hospitalization.Thephysiciancallsthe pharmacyforarecommendationfortreatment ofapresumed

A.Ertapenem B.Ciprofloxacin C.Ceftolozane/tazobactam D.Ceftazidime/avibactam

Characteristic Ceftolozane/tazobactam Ceftazidime/avibactam Pseudomonas activity X X ESBLactivity X X Anaerobicactivity X* Urinarytractinfection XX indication IntraͲabdominal infection XX indication Prolonged infusion X Renal doseadjustment X X

*TreatmentofcomplicatedintraͲabdominalinfection requiresadditionofmetronidazole A38yearoldmanpresentsonSaturday afternoontotheERcomplainingofleftlower extremityerythemaandswellingarounda purulentmassthathasbeenworseningover thepastdays. Relevantlabsandvitals: WBC:12.7x103 cells/mm3 Tmax:38.4C,HR:80bpm,BP:132/91 PMH/:DVT9weeksago—warfarin 6mgPOdaily;depression—fluoxetine40mg daily SH:Livesathomewithwifeand1weekold daughter

InvasiveMRSA 80,000infections/year 11,285deaths/year Mostcommonduringorsoonafterinpatient care AppropriatecentralͲlineprocedureshave reducedratesofinfection

https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_co mbating_antiboticͲresistant_bacteria.pdf SkinIndication OtherIndications Ceftaroline Doxycycline*(IVandPO) Clindamycin*(IVandPO) Sulfamethoxazole/trimethoprim* Dalbavancin (IVandPO) Daptomycin (IVandPO) Oritavancin Quinupristin/dalfopristin Tedizolid(IVandPO) Telavancin Tigecycline

*PrimarilyusedagainstcommunityͲassociatedMRSA(CAͲMRSA)

Conditionsfor whichAntibioticTherapyisRecommendedafterIncisionandDrainage ofanAbscessduetoCommunityͲassociatedMRSA

Severe orextensivediseaseorrapidprogressioninpresenceofassociatedcellulitis Signsand symptomsofsystemicillness Associatedcomorbidities orimmunosuppression Extremesofage Abscessinan difficulttocompletelydrain(face,hand,genitalia) Associatedsepticphlebitis Lackofresponsetoincisionanddrainagealone

LiuC,etal.ClinInfectDis.2011.52:1Ͳ38.

StevensDL,etal.ClinInfectDis.2014.DOI:10.1093/cid/ciu296. Brandname:Sivextro® Pharmacologicclass:oxazolidinone Approvaldate:June20,2014 Manufacturer:Merck Indication:acutebacterialskinandskin structureinfections(ABSSSIs) Dose:200mgIVorPOoncedaily

Mechanism Bacteriostatic Bindsto23SribosomalRNAof50Ssubunit preventingformationofthe70Sinitiationcomplex Pharmacokinetics Greaterthan90%bioavailable HalfͲlife:~12hours Nodosingadjustments Administerwithoutregardtofood Metabolizedbysulfationandeliminatedviathe liver BurdetteSD.ClinInfectDis.2015.DOI:10.1093/cid/civ501.

NoeffectoncytochromeP450(CYP)enzymes Reversibleinhibitorofmonoamineoxidase (MAO) Notevaluatedinphase2or3trials Preclinicalstudiesindicatelessinhibitionthan linezolid Murineheadtwitchmodel

BurdetteSD.ClinInfectDis.2015.DOI:10.1093/cid/civ501. Longestdurationstudied:21daysinhealthy subjects Gastrointestinaleffectsweremostcommon Nosignificanthematologicchangesatcurrent approveddose Phase3studies Nausea Headache Diarrhea

DasD,etal.ClinInfectDis.2014;58(S1):S51Ͳ7.

Staphylococcusaureus(methicillinͲsusceptible andmethicillinͲresistant) Streptococcuspyogenes Streptococcusagalactiae Streptococcusanginosusgroup faecalis Enterococcusfaecium(includingVRE) CoagulaseͲnegativestaphylococci Corynebacteriumjeikeium Someatypicals,somemycobacteria,some anaerobes BurdetteSD.ClinInfectDis.2015.DOI:10.1093/cid/civ501.

StudyName Design PrimaryOutcome Results ESTABLISH I Randomized, doubleͲ Earlyclinical 79.5% intedizolid blind,nonͲinferiority responseat48Ͳ72 armand79.4%in hours linezolidarm Tedizolidvs.Linezolid experiencedearly clinicalresponse N=667 ESTABLISHII Randomized,doubleͲ Greaterthan20% 85% oftedizolid blind,nonͲinferiority reductioninthe patientsand83%of areaofinfectionat linezolidpatients 6daysofIVtoPO 48Ͳ72hours hadearlyclinical Tedizolidvs.10daysof response IVtoPOLinezolid

N=666

ProkocimerP,etal.JAMA.2013;309:559Ͳ569. MoranGJ,etal.LancetInfectDis.2014;14:696Ͳ705. Cysticfibrosis Adolescentswithcomplicatedskininfections Useinobesity Comparedtolinezolidfortreatingnosocomial pneumonia

https://clinicaltrials.gov

Characteristic Linezolid Tedizolid Indication VancomycinͲresistant Acutebacterialskinand enterococcalinfections skinstructureinfections Pneumonia Skinandskinstructure Dosing Frequency Twice daily Oncedaily Dosageform IVandPO IV andPO Adversereactions +++ + Druginteractions ++++ ++ Efficacy = =

Brandname:Dalvance® Pharmacologicclass: Approvaldate:May23,2014 Manufacturer:Actavis Indication:acutebacterialskinandskin structureinfections Dose:1000mgIVx1,followedby500mgx1 oneweeklater Mechanism Bactericidal BindstoDͲalanylͲDͲalanineterminusofcellwall preventcrossͲlinkingof Pharmacokinetics Poororalabsorption HalfͲlife:346hours Extensivelyproteinbound DoseadjustmentforCrCl<30ml/min:750mgx1, followedby375mgx1oneweeklater Noadjustmentforpatientsonhemodialysis

Zhanel,etal.Drugs.2010;70(7):859Ͳ886.

Notasubstrate,inducer,orinhibitorof cytochromeP450isoenzymes Norelevantinteractions

Gastrointestinal Headache Pruritus RedͲmansyndrome ALTelevations

Gurskey,etal.Pharmacotherapy.2010;30(1):80Ͳ94. Zhanel,etal.Drugs.2010;70(7):859Ͳ886. Staphylococci(includingMRSA) Streptococci Enterococci VancomycinͲresistantenterococci VancomycinͲintermediateS.aureus (VISA)

Gurskey,etal.Pharmacotherapy.2010;30(1):80Ͳ94.

StudyName Design PrimaryOutcome Results

DISCOVER1 DoubleͲblind, doubleͲ Earlyclinical 83.3%responsein N=573 dummy,international, responseat48Ͳ72 dalbavancingroup multicenter,randomized hours vs.81.8%in the trial vancomycingroup DISCOVER2 76.8%responsein N=739 Dalbavancin1gramx1 dalbavancingroup followedby500mgon and78.3%inthe day8vs.Vancomycin1 vancomycingroup gram(or15mg/kg)q12hx 3dayswithoptionto switchtolinezolid600mg q12hx10Ͳ14days Pooled 78.7%responsein Analysis dalbavancin group vs.79.8%inthe vancomycingroup

BoucherHW,etal.NEnglJMed.2014;370(23):2169Ͳ2179.

CommunityͲacquiredpneumonia Dalbavancin+azithromycinvs.linezolid+ azithromycin Pediatric

https://clinicaltrials.gov Brandname:Orbactiv™ Pharmacologicclass:lipoglycopeptide Approvaldate:August6,2014 Manufacturer:MedicinesCompany Indication:acutebacterialskinandskin structureinfections Dose:1200mgIVx1doseinfusedover3hours

Mechanism Bactericidal Blockstransglycosylationstepofpeptidoglycan synthesisandinhibitscrossͲlinking Depolarizationandincreasedpermeability Pharmacokinetics Poororalabsorption TerminalhalfͲlife:393hours Highlyproteinbound Tissueelimination Norenalorhepaticdosingadjustments SaravolatzLD.ClinInfectDis.2015;61(4):627Ͳ32.

WeakinhibitororinducerofCYP450 isoenzymes Warfarinconcentrationsmaybeincreased INRmonitoringunreliablewithin24hoursof oritavancinuse

SaravolatzLD.ClinInfectDis.2015;61(4):627Ͳ32. Nausea Headache Vomiting Limbandsubcutaneousabscesses Diarrhea ALTelevations Osteomyelitisconcern

Orbactiv™[packageinsert].Parsippany,NJ:TheMedicinesCompany.2014 SaravolatzLD.ClinInfectDis.2015;61(4):627Ͳ32.

Staphylococcusaureus(MRSAandMSSA) CoagulasenegativeStaphylococcus Streptococcusspp. VancomycinͲresistantenterococci(VRE) Micrococcus spp. Listeriamonocytogenes Corynebacteriumspp. AnaerobicgramͲpositives

SaravolatzLD.ClinInfectDis.2015;61(4):627Ͳ32.

StudyName Design PrimaryOutcome Results SOLOI Randomized,double Cessationofspreadingor 82.3%inthe blind,international reductioninlesionsize, oritavancinarm study(N=954) absence offever,or and78.9%inthe absenceofrescue vancomycinarm 1200 mgoritavancinx1 antibioticsinthe48Ͳ72 achievedearly vs.vancomycin1gor hoursafteroritavancin clinicalsuccess 15mg/kgBIDfor7Ͳ10 days SOLO II Randomized,double Cessationofspreadingor 80.1%inthe blind,international reductioninlesionsize, oritavancinarm study(N=1005) absence offever,or and82.9%inthe absenceofrescue vancomycinarm 1200 mgoritavancinx1 antibioticsinthe48Ͳ72 achievedearly vs.vancomycin1gor hoursafteroritavancin clinicalsuccess 15mg/kgBIDfor7Ͳ10 days

CoreyGR,etal.NEnglJMed. 2014;370:2180Ͳ90. CoreyGR,etal.ClinInfectDis. 2015;60(2):254Ͳ62. Druginteractionstudieswithwarfarin Newformulationadjustinginfusiontime Pediatrics

https://clinicaltrials.gov

Characteristic Dalbavancin Oritavancin One timedose X 30minuteinfusion X Renaldosingadjustment X Druginteractionconcerns X ProlongedhalfͲlife X X

A38yearoldmanpresentsonSaturdayafternoonto theERcomplainingofleftlowerextremityerythema andswellingaroundapurulentmassthathasbeen worseningoverthepastdays. Relevantlabsandvitals: WBC:12.7x103 cells/mm3 Tmax:38.4C,HR:80bpm,BP:132/91 PMH/Medications:DVT9weeksago—warfarin6mg POdaily;depression—fluoxetine40mgdaily SH:Livesathomewithwifeand1weekolddaughter A. Linezolid B. Tedizolid C. Dalbavancin D. Oritavancin

Allagents Restrictions Dosingadjustmentsandinfusiontimeconcerns Indications Oritavancin/dalbavancin Outpatientantibiotictherapy Admissionavoidancepossibility

Futurestudies Newindications Dosingstrategiesandinfusiontimes Newagents Nationalcallforprudentantibioticuse Decreasedactivityofavailableagents Opportunitiesfortreatingresistantorganisms Uniquepropertiesofmedicationsprovides opportunityforpharmacyandstewardship teams

AnnLloyd,PharmD,BCPSͲAQID AssistantProfessor TheUniversityofOklahomaCollegeofPharmacy ClinicalPharmacySpecialistinInfectiousDiseases SaintFrancisHospital Tulsa,OK OSHPFallMeeting October23,2015