treatment of clostridium difficile infec5on · pdf filegeneral principles • treat only...
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Treatment of Clostridium Difficile Infec5on 2017
GunterSchleicherDirector,WitsDGMCICU
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Community vs hospital acquired CDI • Communityacquired
1. Younger2. ExposuretoanCbioCcs3. Acid-suppressionmedicaCon4. EnvironmentalandfoodcontaminaCon5. Contactwithinfectedpersons
• Hospitalacquired1. Riskfactors2. Severity
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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
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Treatment outline • Non-severedisease1. IniCaltherapy2. Recurrentdisease• Severedisease1. AnCbioCcs2. Surgery• Alterna&vetherapies1. ProbioCcs2. Faecalmicrobiotatransplant3. AlternaCveanCbioCcs4. Anion-bindingresins5. Intravenousimmuneglobulin
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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
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How to wash your hands properly
1. Wetyourhandsunderrunningwater
2. Latherwithsoap3. Coverallpartsofyourhands4. Rinsewellunderrunningwater5. Drythoroughly
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Non-severe CDI
• Metronidazole400-800mgtdsPOx10days• Cheap• Upto25%failurerate• ChangetoVancomycinif1. NoclinicalimprovementordeterioraConwithin48hours2. Sideeffects(nausea,rash,neuropathy,alcohol)3. Pregnant4. Children
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Moderate CDI • Indicators:1. DehydraCon(stage1AKINAKI)2. Abdominaltenderness3. WCC>15,albumin<254. Age>60,5. Pyrexial6. PseudomembranouscoliCs
• Treatment:1. SupporCve2. Vancomycin125-250mgPOqidx14days
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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
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Severe CDI - Treatment • SupporCve1. ICU/Highcare2. GoaldirectedfluidresuscitaCon3. Vasopressors,inotropes,corCcosteroids,NGT4. ConsiderTPN5. MonitorIAP6. Surgicalconsult7. ConsiderbroadspectrumanCbioCcsinshockedpaCents
• Specific1. Metronidazole500mgIVtds2. Vancomycin500mgPO/NGT/enema3. Fidaxomicin200mgPObd
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Complicated CDI
• Toxicmegacolon• PeritoniCs• Abdominalcompartmentsyndrome• SuspectedbowelperforaConornecrosis• Refractoryshock• WorseningMOF(AKI,ARDS,delirium,etc)
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Complicated CDI - Treatment
• SupporCve• Specific1. IVMetronidazole+Vancomycin(PO/NGT/colonicirrigaCon)2. ConsiderFidaxomicin200mgPO/NGTbd3. ConsiderTigecycline100mgIVbd4. ConsiderIVIG
• Surgical1. ConsiderifworseningMOForperitoniCs2. Subtotalcolectomywithileostomy(mortalityupto50%)3. DiverCngloopileostomywithVancomycincoloniclavage
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Recurrent CDI
• InabilityofCDItreatmenttoclearspores• SurviveinacidicenvironmentsandcolonicdiverCcula• ResistanttoanCbioCcs• CanpersistduetodisrupConofprotecCvemicrobiota• InadequateproducConofanC-toxinanCbodies• SporesgerminateandconverttovegetaCveform,producetoxin
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Recurrent CDI – risk factors
• Age65y• PreviousepisodesofCdifficileinfecCon• HistoryofsevereCdifficileinfecCon• Increasingperipheralleukocytecount• Hypoalbuminemia• Fever• PresenceofcomorbidcondiCons• Inflammatoryboweldisease• OngoingorrecurrentanCbioCcexposure• DecreasedserumanC–toxinAIgG• UseofacidsuppressionmedicaCons(controversial)
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Recurrent CDI • Firstrecurrence1. Vancomycin125-250mgPOqidx14days2. Fidaxomicin200mgPObdx10days
• Secondandfurtherrecurrence1. Tapered/pulsedoralVancomycinwithProbioCcs2. Fidaxomicin200mgPObdx10days3. Fecalmicrobiotatransplant4. “Rifaximinchaser”400mgPObdx14daysalerVancomycin125mgPOqidx
14days5. IVIG400mg/kgrepeatedupto3Cmes(3weekintervals)
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Fidaxomicin
• NotyetregisteredinSA• MacrolideanCbioCcwithnosystemicabsorpCon• AcCvityagainstgramposiCveaerobicandanaerobicbacteria,includingC.Difficile
• Clinicalefficacysimilartovancomycininmild-moderateCDI• LowerrecurrenceratesamongpaCentswithnon-NAP1strains(19%vs35%)
• AppropriatetherapyinpaCentswithrecurrentCDI,orasiniCaltherapyinpaCentsathighriskofdevelopingrecurrentdisease
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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
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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
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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
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Probio5cs
• ProbioCcsmaybeindicatedforpaCentsreceivinganCbioCcswhoarefelttobeatincreasedriskforCDI
• ThereiscurrentlynodatatosupportadministeringadjuncCveprobioCcsforrouCnetreatmentofCDI
• NodatasupporCngaroleforprobioCcsintreatmentofsevereCDI• ProbioCcsmaybeausefuladjuncCvetherapytoanCmicrobialtherapyforCDIinpaCentswithnon-severerecurrentdisease
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Alterna5ve an5bio5cs
• Nitazoxanide:equivalenttometronidazoleandvancomycin,thecostissignificantlymore,furtherstudiesareneededtoassessthismedicaConasanalternateinthetreatmentofseveredisease
• Tigecycline:maybeanopConforsevere,complicateddiseaseincriCcallyillpaCentsincombinaConwithotherCDItherapies
• Rifaximin:sequenCaltherapywithvancomycinfollowedbyrifaximinmaybeeffecCveforthetreatmentofrecurrentCDI
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Anion-binding resins
• Coles&pol(5gevery12hours)orCholestyramine(4g3-4xdaily)for1-2weeks
• NoteffecCveasprimarytherapyforCDI,althoughtheymaybebeneficialasadjuncCvetherapyforrelapsinginfecCon
• Anion-exchangeresinsbindVancomycinaswellasC.difficiletoxins• TolevamerisaC.difficiletoxin-bindingresindevelopedspecificallyforCDI,inferiortobothVancomycinandMetronidazoleasprimarytherapy
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Immunotherapy • PooledIVIG1. ContainsC.difficileanCtoxin(IgGanC-toxinAAbs)2. Mayhavearoleinrelapsing,severeorfulminantCDIinaddiConto
anCbioCctherapy• Bezlotoxumab1. HumanmonoclonalanCbodiesagainstC.difficiletoxinB2. InpaCentsreceivinganCbioCctreatmentforprimaryor
recurrentC.difficileinfecConbezlotoxumabwasassociatedwithasubstanCallylowerrateofrecurrentinfecCon(clinicalcurewithoutrecurrentinfecConin12weeks64%vs54%)
3. Expensive
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Thank you!
Ques5ons?
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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)