Treatment of Clostridium Difficile Infec5on 2017

GunterSchleicherDirector,WitsDGMCICU

Community vs hospital acquired CDI • Communityacquired

1.  Younger2.  ExposuretoanCbioCcs3.  Acid-suppressionmedicaCon4.  EnvironmentalandfoodcontaminaCon5.  Contactwithinfectedpersons

• Hospitalacquired1.  Riskfactors2.  Severity

Hospital acquired CDI – risk factors •  Age65y•  PrevioushospitalizaConandprolongedlengthofhospitalstay

•  Nursinghomeorlong-termcarefacilityresidence

•  ContactwithacCvecarriers•  An&bio&cexposure(fluoroquinolones)•  IncreasedriskwithprolongeduseormulCpleanCbioCcs

•  ConsumpConofprocessedmeat•  PreviousgastrointesCnalsurgeryorendoscopicprocedure

•  Presenceofcomorbidcondi&ons• Malignancyandchemotherapy•  CysCcfibrosis

•  Diabetesmellitus•  Livercirrhosis•  Chronickidneydisease•  Inflammatoryboweldisease•  Immunosuppression,immunodeficiency,orhumanimmunodeficiencyvirus

•  MalnutriCon•  Hypoalbuminemia•  Useofprotonpumpinhibitors•  SolidorganorhematopoieCcstemcelltransplantaCon

•  Presenceofgastrostomyorjejunostomytube

Treatment outline • Non-severedisease1.  IniCaltherapy2.  Recurrentdisease•  Severedisease1.  AnCbioCcs2.  Surgery• Alterna&vetherapies1.  ProbioCcs2.  Faecalmicrobiotatransplant3.  AlternaCveanCbioCcs4.  Anion-bindingresins5.  Intravenousimmuneglobulin

General principles

•  Treatonlysymptoma&cpaCents•  Earlyrecogni&onofhighriskpaCentsandpromptdiagnosis•  StopormodifyinciCngan&bio&cs•  IfanCbioCcsaresCllnecessarytrytouseaminoglycosides,macrolides,vancomycin,Cgecycline

•  Strictinfec&oncontrol(isolaCon,washhandswithsoapandwater)• AvoidanCmoClityagentse.g.loperamide,opiods•  Suppor&vecare,fluidresuscitaCon,correctelectrolyteimbalances,nutriConalsupport

•  Surgery

How to wash your hands properly

1.  Wetyourhandsunderrunningwater

2.  Latherwithsoap3.  Coverallpartsofyourhands4.  Rinsewellunderrunningwater5.  Drythoroughly

Non-severe CDI

• Metronidazole400-800mgtdsPOx10days• Cheap• Upto25%failurerate• ChangetoVancomycinif1.  NoclinicalimprovementordeterioraConwithin48hours2.  Sideeffects(nausea,rash,neuropathy,alcohol)3.  Pregnant4.  Children

Moderate CDI •  Indicators:1.  DehydraCon(stage1AKINAKI)2.  Abdominaltenderness3.  WCC>15,albumin<254.  Age>60,5.  Pyrexial6.  PseudomembranouscoliCs

•  Treatment:1.  SupporCve2.  Vancomycin125-250mgPOqidx14days

Severe CDI – risk factors •  Age>65y•  AnCperistalCcornarcoCcmedicaConuse•  Underlyingcomorbidcondi&ons•  Immunosuppressivemedica&onuse•  Acutekidneyinjuryorchronickidneydisease•  ChronicobstrucCvepulmonarydisease•  Alteredmentalstatus•  Fever•  Hypotension•  Severeabdominalpainand/ordistenCon•  Tenormorebowelmovementsperday•  Leukocytosis(WCC>20)•  Hypoalbuminemia•  Ileus•  Presenceofpseudomembranes

Severe CDI - Treatment •  SupporCve1.  ICU/Highcare2.  GoaldirectedfluidresuscitaCon3.  Vasopressors,inotropes,corCcosteroids,NGT4.  ConsiderTPN5.  MonitorIAP6.  Surgicalconsult7.  ConsiderbroadspectrumanCbioCcsinshockedpaCents

•  Specific1.  Metronidazole500mgIVtds2.  Vancomycin500mgPO/NGT/enema3.  Fidaxomicin200mgPObd

Complicated CDI

•  Toxicmegacolon• PeritoniCs• Abdominalcompartmentsyndrome•  SuspectedbowelperforaConornecrosis• Refractoryshock• WorseningMOF(AKI,ARDS,delirium,etc)

Complicated CDI - Treatment

•  SupporCve•  Specific1.  IVMetronidazole+Vancomycin(PO/NGT/colonicirrigaCon)2.  ConsiderFidaxomicin200mgPO/NGTbd3.  ConsiderTigecycline100mgIVbd4.  ConsiderIVIG

•  Surgical1.  ConsiderifworseningMOForperitoniCs2.  Subtotalcolectomywithileostomy(mortalityupto50%)3.  DiverCngloopileostomywithVancomycincoloniclavage

Recurrent CDI

•  InabilityofCDItreatmenttoclearspores•  SurviveinacidicenvironmentsandcolonicdiverCcula• ResistanttoanCbioCcs• CanpersistduetodisrupConofprotecCvemicrobiota•  InadequateproducConofanC-toxinanCbodies•  SporesgerminateandconverttovegetaCveform,producetoxin

Recurrent CDI – risk factors

•  Age65y•  PreviousepisodesofCdifficileinfecCon•  HistoryofsevereCdifficileinfecCon•  Increasingperipheralleukocytecount•  Hypoalbuminemia•  Fever•  PresenceofcomorbidcondiCons•  Inflammatoryboweldisease•  OngoingorrecurrentanCbioCcexposure•  DecreasedserumanC–toxinAIgG•  UseofacidsuppressionmedicaCons(controversial)

Recurrent CDI •  Firstrecurrence1.  Vancomycin125-250mgPOqidx14days2.  Fidaxomicin200mgPObdx10days

•  Secondandfurtherrecurrence1.  Tapered/pulsedoralVancomycinwithProbioCcs2.  Fidaxomicin200mgPObdx10days3.  Fecalmicrobiotatransplant4.  “Rifaximinchaser”400mgPObdx14daysalerVancomycin125mgPOqidx

14days5.  IVIG400mg/kgrepeatedupto3Cmes(3weekintervals)

Fidaxomicin

• NotyetregisteredinSA• MacrolideanCbioCcwithnosystemicabsorpCon• AcCvityagainstgramposiCveaerobicandanaerobicbacteria,includingC.Difficile

• Clinicalefficacysimilartovancomycininmild-moderateCDI•  LowerrecurrenceratesamongpaCentswithnon-NAP1strains(19%vs35%)

• AppropriatetherapyinpaCentswithrecurrentCDI,orasiniCaltherapyinpaCentsathighriskofdevelopingrecurrentdisease

0

20

40

60

80

100

Clinical cure

Recurrence Sustained clinical cure

Clinical cure

Recurrence Sustained clinical cure

Fidaxomicin

Vancomycin

1.EuropeanPublicAssessmentReport,22September2011(EMA/857570/2011);2.LouieTJ,etal.NEnglJMed2011;364:422–31;3.CornelyOA,etal.LancetInfectDis2012;12:281–9.

88.2

253/287Su

bjectsachievingend

point(%)

265/309

39/253

67/265

214/287

198/309

221/252

223/257

28/221

60/223

193/252

163/257

85.8

15.4

25.3

74.6

64.1

87.7 86.8

12.7

26.9

76.6

63.4

Difference(confidenceinterval)

[Pvalue]

0031,2 0043

Datafrommodifiedintent-to-treatpopulaCon

NS,notsignificant;

Study003:USA,Canada;Study004:Belgium,Canada,

France,Germany,Italy,Spain,Sweden,UK,USA

2.4(–3.1,7.8)[P=NS]

10.5(3.1,17.7)[P=0.0006]

–9.9(–16.6,–2.9)[P=0.005]

–14.2(–21.4,–6.8)[P=0.0002]

13.2(5.2,20.9)[P=0.001]

0.9(–4.9,6.7)[P=NS]

ComparisonoffidaxomicinwithvancomycinonclinicalcureofCDI,prevenConofrecurrence,andsustainedcure

FromTheNewEnglandJournalofMedicine,TJLouie,MAMiller,KMMullane,KWeiss,ALentnek,YGolan,SGorbach,PSears,Y-KShue,fortheOPT-80-003ClinicalStudyGroup,FidaxomicinversusVancomycinforClostridiumdifficileInfecCon,364,422-31.Copyright©2011MassachusevsMedicalSociety.ReprintedwithpermissionfromMassachusevsMedicalSociety.Copyright©2011,MassachusevsMedicalSocietyReprintedfromLancetInfectDis,12,OACornely,DWCrook,REsposito,APoirier,MSSomero,KWeiss,PSears,SGorbach,fortheOPT-80-004ClinicalStudyGroup,FidaxomicinversusvancomycinforinfecConwithClostridiumdifficileinEurope,Canada,andtheUSA:adouble-blind,non-inferiority,randomisedcontrolledtrial,281-89,Copyright(2012),withpermissionfromElsevier.hvp://www.thelancet.com/journals/laninf/issue/current

Faecal microbiota transplant

•  Indicatedformildorcomplicateddisease,recurrentCDI•  OralorrectaltransplantaConoffaecesfromahealthy,pretesteddonorandthesimultaneouscessaConofallanCbioCcuseintherecipientaresuccessfulintreaCngmorethan90%ofpaCentswithrecurrentC.difficileinfecCon

•  RiskoftransmissionofinfecCousagentscanbeminimisedbyobtainingstoolfromhealthydonorswithnormalbowelfuncConandbytesCngbothstoolandbloodforcommonviralandbacterialpathogensandparasites

•  DonortesCng:1.  Blood: CMV, EBV, HAV, HBV, HCV, HEV, Syphilis, HIV, Entamoeba histolytica, FBC, CRP,

Albumin, U&E, LFT

2.  Stool: Clostridium difficile, Salmonella, Shigella, Campylobacter, Escherichia coli O157 H7, Yersinia, VRE, MRSA, MDR-GNB, Norovirus, Giardia lamblia and Criptosporidium parvum, Protozoa and helminths, Faecal occult blood testing

Faecal microbiota transplant - Protocol •  StoolpreparaCon:usefreshstoolwithin6hours/frozen•  TreatpaCentswithvancomycinorfidaxomicinatleastfor3daysbeforeFMT.AnCbioCcsshouldbestopped12–48hoursbeforefaecalinfusion

• PPIusedifstooldeliveredbyNGT• DonorstoolcanbedeliveredbyC-scope,enema,G-scope,NGT,NJT/capsule

•  FrozenFMTnon-inferiortofreshFMT•  FMTappearstobesafeeveninimmunocompromisedandcriCcallyillpaCentsregardlesstherouteofdelivery-faecalinfusionbyenema(s)preferred

Probio5cs

• ProbioCcsmaybeindicatedforpaCentsreceivinganCbioCcswhoarefelttobeatincreasedriskforCDI

•  ThereiscurrentlynodatatosupportadministeringadjuncCveprobioCcsforrouCnetreatmentofCDI

• NodatasupporCngaroleforprobioCcsintreatmentofsevereCDI• ProbioCcsmaybeausefuladjuncCvetherapytoanCmicrobialtherapyforCDIinpaCentswithnon-severerecurrentdisease

Alterna5ve an5bio5cs

• Nitazoxanide:equivalenttometronidazoleandvancomycin,thecostissignificantlymore,furtherstudiesareneededtoassessthismedicaConasanalternateinthetreatmentofseveredisease

•  Tigecycline:maybeanopConforsevere,complicateddiseaseincriCcallyillpaCentsincombinaConwithotherCDItherapies

• Rifaximin:sequenCaltherapywithvancomycinfollowedbyrifaximinmaybeeffecCveforthetreatmentofrecurrentCDI

Anion-binding resins

• Coles&pol(5gevery12hours)orCholestyramine(4g3-4xdaily)for1-2weeks

• NoteffecCveasprimarytherapyforCDI,althoughtheymaybebeneficialasadjuncCvetherapyforrelapsinginfecCon

• Anion-exchangeresinsbindVancomycinaswellasC.difficiletoxins•  TolevamerisaC.difficiletoxin-bindingresindevelopedspecificallyforCDI,inferiortobothVancomycinandMetronidazoleasprimarytherapy

Immunotherapy • PooledIVIG1.  ContainsC.difficileanCtoxin(IgGanC-toxinAAbs)2.  Mayhavearoleinrelapsing,severeorfulminantCDIinaddiConto

anCbioCctherapy• Bezlotoxumab1.  HumanmonoclonalanCbodiesagainstC.difficiletoxinB2.  InpaCentsreceivinganCbioCctreatmentforprimaryor

recurrentC.difficileinfecConbezlotoxumabwasassociatedwithasubstanCallylowerrateofrecurrentinfecCon(clinicalcurewithoutrecurrentinfecConin12weeks64%vs54%)

3.  Expensive

Thank you!

Ques5ons?

Cost Vancomycin 1gram vial 14 vials (R176.85) R2475.98

Metronidazole 400mg tablets 3 x 14 = 42 tablets (R5.09) R213.95

Tigecycline 50mg vials 2 + 2 x 14 = 30 vials (R891.77) R26753.25

IVIG 30g x 5 = 150g (R12130.02) R60650.10

Cholestyramine 4 gram sachet 4 x 14 = 56 (R7.47) R418.62

Fidaxomycin 200mg tablets 10 x 2 = 20 R?

Bezlotoxumab 10 mg/kg x 1 USD17000 (R238000)