Pharmacologic treatment of Clostridium difficile infection - Doppelganger? Chris Gentry, Pharm.D., BCPS Chief, Pharmacy Service Oklahoma City VA ...

Pharmacologictreatmentof
              Clostridiumdifficile infection

ChrisGentry,Pharm.D.,BCPS
Chief,PharmacyService
OklahomaCityVAHealthcareSystem

                         Doppelganger?

Outline
• ReviewepidemiologyofClostridiumdifficileinfections(CDI)
• DescribetheclinicalpresentationanddiagnosisofCDI
• Reviewcharacteristicsofcommonantibacterialagentsinvolvedin
  thetreatmentofCDI
• BrieflydiscussmanagementoffirstepisodesofmildͲmoderateCDI
• DiscussmanagementofsevereepisodesofCDI
• DescribemanagementofrecurrentCDI
• DebatenonͲantibacterialstrategiesplaceintherapy

Clostridiumdifficilecharacteristics
•   SporeͲforming,anaerobicGrampositivebacillus(rod)
•   Cancolonizeintestinaltract
•   Sporesfoundonenvironmentalsurfaces
•   Sporesresistanttoalcoholpreparations

                                                   CDC

                        CDIEpidemiology
• Clostridiumdifficileisthemostcommoncauseofinfectious
  diarrheainhealthcaresettings.
• NHSN pooled rate of hospital-onset CDI is at least 7.4 per
  10,000 patient-days.
• Approximately 453,000 cases in 2011:
    – 64.7% healthcare-associated
    – 37% hospital onset
    – 36% long-term care facilities (LTCFs)
• Several characteristics, such as spore formation, allow the
  organism to be horizontally-transferred between patients and
  healthcare workers
                                                 CID2018CDIGuidelines
                                              MMWRMorb MortalWkly Rep.2012

IncidenceofNosocomialC.difficileInfection

                                                         Leffler et al. NEJM
                                                         2015:372;16

              EpidemiologyͲ Recurrence
• Recurrenceoccursinapproximately20Ͳ30%ofpatientswho
  developCDI.
  – Subsequentrecurrencesunacceptablyhighaswell.
  – Fewtreatmentstrategiesshowntoreducetherecurrencerate.
• Zilberberg etalfoundthat33%of15,000medicare nursing
  homepatientswithCDIrecurred,associatedwith2more
  hospitalizationsperpatientand20.3excesshospitaldays.

                                                 Zilberbergetal.Medicine2017

EmergenceoftheC.difficileBI/NAP1/027strain
• ThisstrainemergedwiththeincreasingincidenceofCDIin
  early2000’s
• Prevalencedatafrom2000Ͳ2010indicatedmediansof~25Ͳ
  30%,ashighas~40%,ofCDIstrainswereBI/NAP1/027
• UKwitnessedthisincreaseaswell,butrecentlydemonstrated
  asharpdecline
• Arewestartingtoseeadeclineaswell?

C.difficileBI/NAP1/027strain
                   RecentRegionaltrends

Geographicmapofthe
prevalenceoftheC.
difficileBI/NAP1/027
strain.

Blackш25%
Darkgrey=20Ͳ24.9%
Lightgrey

C.difficileinfection pathogenesis
Colonization
                Riskfactormodifiers:
                     Antibiotics
                   AdvancedAge
                     GIsurgery
                Acidsuppression,etc

                                         Abnormalcolonic
                                           microbiota

                                                              SelectionofC.difficile
                                                             growthandactivationof
                                                                 toxinproduction

                                                                                             Diarrhea
                                                                                            andcolitis

                         CDI– primaryriskfactors
  • Anyantibacterialuse
      – Broadspectrumuseinparticular
      – Fluoroquinolonesandclindamycinmostoftenimplicated
  •   Age>65years
  •   Recenthospitalization
  •   Useofprotonpumpinhibitors/gastricacidsuppression
  •   Enteralfeeding
  •   Recentgastrointestinalsurgery
  •   Bonemarrowtransplantation
  •   Inflammatoryboweldisease
  •   Recentcancerchemotherapy

CDIclinicalpresentation
• Symptoms:
  – Diarrhea
       • Watery
       • ш3loosestoolsin24hours
       • Mayincludesomeoccultblood
  –   Lowerabdominalpain/cramping
  –   Fever/chills
  –   Weightloss
  –   Nausea
  –   Anorexia

                    CDIclinicalpresentation
• Signs:
  – Leukocytosis
  – Elevatedbloodureanitrogen
  – Elevatedserumcreatinine
  – Elevatedlacticacid
  – Radiologicevidenceofcolitis
  – Colonoscopyevidenceoffriablepseudomembranouscolitis

Colonoscopy
Normal                                  CDI

         https://gastrolab.net           https://commons.wikimedia.org/wiki/File:Pseudom
                                         embranous_colitis_1.jpg

                       CDIclinicalpresentation
                    SevereandSevereComplicated
• SevereCDI:
  – Leukocytosis>15,000cells/mm3
                           OR
  – Serumcreatinine1.5x>baseline
• SevereComplicated(nowFulminant)CDI:
  – Fulminantcolitis
  – Ileus
  – Toxicmegacolon

C.Difficilediagnosis
• Patients with unexplained and new-onset •3 unformed
  stools in 24 hours should be tested for CDI
  – Check if receiving laxatives, enteral feedings, etc.
• Nucleic acid amplification test (NAAT or polymerase chain
  reaction {PCR}) alone is sufficient with appropriate
  specimens

                       Diagnostictests

Diagnostictests

CDITREATMENT

CDItreatment– BrokenupbytypeofCDI
• Initialepisode
   – Mildtomoderate(now“nonͲsevere”inlatestguidelines)
   – Severe
   – Fulminant
• Recurrences
   – First
   – Second/subsequent

   CDItreatment– initialepisode,nonͲsevere
• Vancomycin125mgPOQIDx10
  days
            OR
• Fidaxomicin200mgPOBIDx10
  days

• Alternative:Metronidazole500
  mgPOTIDx10days

Whathappenedtometronidazole?

2014Tolevamer
    study

2014Tolevamer
    study

IDSAMetronidazoleSummary
• “Useoforalmetronidazole,however,shouldberestrictedto
  aninitialepisodeofnonsevere CDIincaseswhereother
  therapiesarecontraindicatedornotavailable,andtreatment
  shouldbelimitedtoonecourseduetocasereportsof
  neurotoxicitywithprolongedorrepeateduse.”

                  AWPfortreatmentcosts
                                     AWPpercourse

     Metronidazoleoraltablets          $20
     500mgPOTIDx10days
     Vancomycinoralcapsules125     $500Ͳ>1,000
     mgPOQIDx10days
     Fidaxomicinoraltablets            $4,418
     200mgPOBIDx10days
     Bezlotoxumab 1,000mgvial          $4,560
     (10mg/kgx1)

CDItreatment– initialepisode,severe
• Vancomycin125mgPOQIDx10
  days
            OR
• Fidaxomicin200mgPOBIDx10
  days

                                         https://www.flickr.com/photos/tareqsalahuddin/7272610736
                                         nochanges

     CDItreatment– initialepisode,fulminant
• Vancomycin500mgQIDby
  mouthorbynasogastrictube.
   – Ifileus,consideraddingrectal
     instillationofvancomycin.
• Metronidazole500mgIVQ8H
  shouldbeadministeredtogether
  withoralorrectalVAN,
  particularlyifileusispresent.

                                         https://commons.wikimedia.org/wiki/File:Cardiac_operating_room.jpg

VancomycinvsFidaxomicinforSevereCDI
• 10,488CDIseverecoursestreatedwitheitheravancomycinͲ
  containingregimenorfidaxomicinfrom6/2011thru6/2017
  across130VAMedicalCenters
  – 10,165vancomycinͲcontainingregimens
  – 323fidaxomicinregimens
• WehavepropensityͲmatchedthevancomycinregimenstothe
  fidaximicin regimensina3:1ratio

   VancomycinvsFidaxomicinforSevereCDI
• 10,488CDIseverecoursestreatedwitheitheravancomycinͲ
  containingregimenorfidaxomicinfrom6/2011thru6/2017
  across130VAMedicalCenters
  – 10,165vancomycinͲcontainingregimens
  – 323fidaxomicinregimens
• WehavepropensityͲmatchedthevancomycinregimenstothe
  fidaximicin regimensina3:1ratio

CDItreatment,firstrecurrence
Firstepisode        Firstrecurrence

                      Vancomycin125
                      mgPOQIDx10
  Vancomycin          days,thentaper

                     Fidaxomicin200mg
                       POBIDx10days

                    Vancomycin125mg
 Metronidazole
                     POQIDx10days

CDItreatment,Secondorsubsequentrecurrence
•   Vancomycintaperorpulse
•   Vancomycinstandardregimenfollowedbyrifaximinx20days
•   Fidaxomicinstandardregimen
•   Fecalmicrobiotatransplantation(after3roundsof
    antimicrobialtherapy)

    CDIRECURRENCE:
    VANCOMYCINVSFIDAXOMICIN

CDIRECURRENCE:
VANCOMYCINVSVANCOMYCINTAPER

TaperEvidence:
        Acoupleofcaseseriesfrom20Ͳ30yearsago

• Recurrenceratesfor“low”(n=48),“medium”(n=14),and“high”(n=21)
  nonͲtaperoralvancomycindosegroupswere54%,71%,and43%,
  respectively.
• Aseparategroupreceivingataperregimen(n=29)hada31%recurrence
  rate.
• Nobaselineevaluationwasdonetodescribecomparabilityofthegroups.

VancomycinTaper– Roleinrecurrence

  Vancomycinstandardvstaper– Gentry2017
• 4,135firstorsecondrecurrenceepisodestreatedsuccessfullywith
  vancomycin.
  – 3,908vancomycinstandardregimens
  – 227vancomycintaperregimens
• Independentvariablesassociatedwiththeselectionofataper
  regimenincluded:
  –   secondrecurrenceepisode(OR,1.83;95%CI,1.33–2.43;p

Propensityeffect

     Propensitycohortbaselinecharacteristics
•   Predominatelymalepopulation
•   Meanage68.8± 12.5years
•   Highincidenceofcomorbidconditions
•   Firstrecurrences70.5%
•   Inpatient37.4%
    – Only4.76%ofepisodeswereclassifiedassevere.
• 80.0%initiallytreatedwitha500Ͳmgtotaldailydoseoforal
  vancomycin

Results;vancomycintapervsstandardregimens

CDIRECURRENCE:
VANCOMYCINTAPERVSFIDAXOMICIN

CDIRECURRENCE:
VANCOMYCINTAPERVSFIDAXOMICIN

CDIRECURRENCE:
ADJUNCTIVEBEZLOTOXUMAB

Bezlotoxumab
• Actoxumab andbezlotoxumab;humanIgG1monoclonalantibodies
  thatbindandneutralizeC.difficiletoxinsAandB,respectively
  – PhaseIIItrialshowednoaddedbenefitofActoxumab,sothisdrugwasno
    longerpursued
• Preclinicaldatasuggeststhatbezlotoxumab reducesproͲ
  inflammatoryandhistologicdamagefromC.difficiletoxinrelease.
• Administeredasasingle10mg/kgIVdoseduringacourseof
  antibacterialtreatmentofaCDIepisode
• Therapeuticplasmalevelsareseenupto84daysafter
  administration(HalfͲlife=19days!)

Bezlotoxumab PhaseIIItrial
               PreventionofCDIrecurrence
• MODIFYIandIIRCCTin30countries
• Participants:
  – AdultsreceivingstandardͲofͲcareantibacterialagentsforCDI
• Randomlyassignedtobezlo,acto,both,orneither(ie,placebo)
• Primaryendpoint:proportionofparticipantswithrecurrent
  CDIduring12weeksoffollowͲupinanMITTpopulation

CDIRECURRENCE:
FECALMICROBIOTATRANSPLANTATION

American
Gastroenterological
   Assocation:

                     FMTͲ FDAguidance
 • “Centralizedmanufacturinginstoolbankspresentssafetyconcerns
   relatedtotheuseofFMTfromalimitednumberofdonors
   administeredtomultiplepatients….
 • Thesesafetyconcernsincludetransmissionofinfectiousagentsand
   potentiallyotherunidentifiedrisksrelatedtochangesinthe
   microbiome….
 • Thesponsor’scompliancewiththeINDrequirementswillhelpto
   ensurethatthestooldonorandstoolareappropriatelyqualifiedby
   screeningandtestingandthatcentralizedprocessingofFMT
   adherestoappropriatecurrentgoodmanufacturingconditions.”

FMTͲ FDAguidance
• FDAwillutilizediscretioninthefollowingcircumstances:
   – Thelicensedhealthcareprovidertreatingthepatientobtainsadequate
     consentfromthepatientorhisorherlegallyauthorizedrepresentativefor
     theuseofFMTproduct.Theconsentshouldinclude,ataminimum,a
     statementthattheuseofFMTproductstotreatC.difficileis
     investigationalandadiscussionofitsreasonablyforeseeablerisks.
   – TheFMTproductisnotobtainedfromastoolbank.
   – Thestooldonorandstoolarequalifiedbyscreeningandtestingperformed
     underthedirectionofthelicensedhealthcareproviderforthepurposeof
     providingtheFMTproducttotreathisorherpatient

  CDIRECURRENCE:
  PROBIOTICS

Theroleofprobioticsforprimaryorsecondary
                   preventionofCDI
• 2010IDSAguidelines:
   – “Administrationofcurrently
     availableprobioticsisnot
     recommendedtopreventprimary
     CDI,astherearelimiteddatato
     supportthisapproachandthereis
     apotentialriskofbloodstream
     infection.”
   – “Thereisnocompellingevidence
     thatotherprobioticsareusefulin
     thepreventionortreatmentof
     recurrentCDI.”

    Theroleofprobioticsforprimaryorsecondary
                   preventionofCDI
• TworecentmetaͲanalysesdemonstratecloseto60%reduction
  inthedevelopmentofCDIinvariouspopulationsreceiving
  probiotics.
   – ShenNTetal.Gastroenterology2017;152:1889.
   – LauCSMetal.Int JGenMed2016;9:27.

ProbioticsͲ Shenetal
• TheincidenceofCDIintheprobioticcohort,1.6%(54of3277),was
  lowerthanofcontrols,3.9%(115of2984)(P

2018IDSAGuidelinesstanceonprobiotics
• “Thereareinsufficientdataatthistimetorecommend
  administrationofprobioticsforprimarypreventionofCDI
  outsideofclinicaltrials.”
• “SeveralprobioticsincludingSaccharomycesboulardii and
  Lactobacillusspecieshaveshownpromiseforthepreventionof
  CDIrecurrence.However,asyet,nonehasdemonstrated
  significantandreproducibleefficacyincontrolledclinical
  trials.”

                        Conclusions
• 2018guideline’sdismissalofmetronidazoleforinitial
  treatmentofnonsevere episodesisabitcontroversialand
  raisespotentialchallenges
• Standardcoursestendtobeeffectiveintreatingeachepisode,
  butwecan’tseemtoknockrecurrenceratesbelow15Ͳ20%at
  best.
• Wewon’tgetfarwithpreventionofCDIwithouttakingcareof
  therecurrenceproblem.

Questions?