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A u g us t 16 -­‐ 1 7 th , 2014 AGA F r e st o n Confe rence Chi cag o , IL. D ISCLOS U RES. Y o u r n ame: Elain e O. Petr o f Th e n ame o f th e c o mmerc ial in tere st(s) : N ubi y o ta

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d isclos u res
DISCLOSURES
  • Your name: Elaine O.Petrof
  • The nameof thecommercial interest(s):Nubiyota
  • The natureof therelaOonship the person has witheach commercial interest: Co-­‐Founder and ScienOficAdvisor.
  • Income (to self or to lab research support): does not exceed$50,000
cme qu e s o o n 1
CME: quesOon #1
  • 76yr old woman with a history of diabetes mellitus type2 and hypertension is admi[ed to Hospital with 4 days of profusewatery diarrhoea. Shewas recentlytreated forC.difficileinfecOon threemonths previouslywith a 10-­‐daycourse of metronidazole 500mgOd for10days. Sheresponded and had formed stools ,5 days a^er iniOaOon of therapy. She did well unOl 4 days ago with therecurrence of her symptoms. She nowhas 10 bowel movements a day associated with diffusecrampy abdominal pain. OnexaminaOon she has a temperature of 38.2 C, pulse115/min, blood pressure125/65,normal cardiac and respiratoryexam. Her abdomen is tender butwith no guarding or rebound. InvesOgaOons show a WBC 15K, Hb112,Plts 332,Na 132,K3.3,Bun 5.4, Creat 200(eGFR20). An abdominal X-­‐ray shows a transversecolon dilated to 5cm.
  • Which is themost appropriatetreatment:
    • 1. Metronidazole500mg po Od x 14 days
    • 2. Vancomycin 125mgpo qid x 14 days
    • 3. Vancomycin 250mg IV q6h X 14 days
    • 4. Stool Transplant
    • 5. Flagyl 500mg IV Od
cme qu e s o o n 11
CME: quesOon #1

Correct Response:2. Vancomycin 125mgpo qid x 14 days

Tes-ng point: determinecorrecttreatment in a paOentwithC. difficileinfecOon based on lab criteria and clinical presentaOon (severity of illness)

Based on levels of clinical evidence and on the IDSAguidelines, “Treatment of the firstrecurrence of CDI is usuallywith thesameregimen as for the iniOal episode(A-­‐II)but should be straOfied by disease severity (mild-­‐to-­‐moderate, severe, orseverecomplicated)”. Based on guidelines, her lab criteria (WBC>12,000,creaOnine) would classify her as severe, but she is not hypotensive and does not have toxicmegacolon so shewould not beconsidered to be severecomplicated CDI. Therefore,correctresponsewould be (2). Theguidelines state “use ofvancomycin is recommended for the firstrecurrencein paOents with a white blood cell count of 15,000cells/μL or higher (or a rising serumcreaOnine level), since theyareathigherrisk of developingcomplicaOons.” The dosage forvancomycin in severe CDI is 125mg orally4Omes per day for10–14 days (B-­‐I)

(1) is incorrect as this paOentwould not beclassified as a mild CDI, (5) is incorrect for the samereason (and in addiOon one would givemetronidazole po, iv is less effecOve)

Since thisisher firstrecurrence,FMT would only beconsidered a^er a second recurrence had failed avancomycin taper orpulseregimen according to currentguidelines, therefore (4) is incorrect. (Note:Metronidazole should not be used beyond the firstrecurrence of CDI or for long-­‐termchronic therapy because of potenOal forcumulaOve neurotoxicity(B-­‐II).

Treatment of the second or laterrecurrence of CDIwithvancomycin therapy using a tapered and/or pulseregimen is the

preferred next strategy(B-­‐III).)

This paOent does not have hypotension or ileus,would not beclassified as severecomplicated and would notrequire vancomycin dosing above125mg po q6h, therefore (3) is incorrect. For severe,complicated CDI,vancomycin administered orally (and perrectum, if ileus is present) with orwithout intravenously administered metronidazole is theregimen ofchoice. In addiOon, thevancomycin dosage is 500mg orally4Omes per day and 500mg in approximately100mL normal saline perrectumevery6 hours as a retenOon enema, and themetronidazole dosage is 500mg intravenouslyevery8 hours(C-­‐III).

REFERENCE:Clinicalprac-ceguidelines for Clostridiumdifficileinfec-oninadults:2010updatebythesocietyforhealthcareepidemiologyof America(SHEA)andthe infec-ousdiseasessocietyof America(IDSA).Cohen SH,GerdingDN,JohnsonS,KellyCP, Loo VG,McDonald LC,Pepin J,Wilcox MH; Society forHealthcare Epidemiology of America; InfecOous Diseases Society ofAmerica. Infect ControlHosp Epidemiol. 2010May;31(5):431-­‐55.

cme qu e s o o n 2
CME: quesOon #2
  • Which of the following isnot a risk factor for the development ofClostridium difficileinfecOon?
    • 1. Moxifloxacin
    • 2. Recent hospitalizaOon
    • 3. Pantoprazole
    • 4. Previous appendectomy
    • 5. AtorvastaOn
cme qu e s o o n 21
CME: quesOon #2

Correct Response:5. AtorvastaOn

Tes-ng point:recognizewhich factors are likelyNOT to be potenOal risk factors for the development ofClostridiumdifficile

infecOon

Of all of the factors listed here, atorvastaOn (opOon 5) is the only one that hasnot been associated with an increased risk of CDI and itmayeven be protecOve (seereferences below).

The singlemost importantmodifiablerisk factor for the development of CDI is exposure to anOmicrobial agents. Even verylimited exposure (e.g., single-­‐dose surgical anObioOc prophylaxis), increases a paOent’s risk of developing CDI, therefore (1) is incorrect.

DuraOon of hospitalizaOon is a risk factor for CDI; therefore (2) is incorrect. In fact, the daily increase in therisk ofC. difficileacquisiOon during hospitalizaOon suggests that duraOon of hospitalizaOon is a proxy for the duraOon, if not the degree, ofexposure to the organism from other paOents with CDI.

Several studies have suggested an epidemiologic associaOon between use of stomach acid–suppressingmedicaOons,primarily proton pump inhibitors, and CDI, therefore (3) is incorrect.

Previous appendectomy has been associated with development of recurrent CDI, therefore (4) is incorrect.

REFERENCES:

Sta-nuse andthe riskof Clostridium difficile inacademic medicalcentres. Motzkus-­‐Feagans CA,Pakyz A,PolkR,GambassiG,LapaneKL. Gut. 2012Nov;61(11):1538-­‐42.

Dosta-nsprotect againstthe developmentof Clostridium difficile-­‐associateddiarrhoea? NseirW,Bishara J,Mograbi J,Mahamid M,Khalaila W, Taha M, Farah R. JAn9microb Chemother. 2013Aug;68(8):1889-­‐93.

The effects ofsta-nsonthe clinicaloutcomes ofClostridiumdifficileinfec-oninhospitalisedpa-ents.Park SW, Choi AR,LeeHJ, ChungH,ParkJC, Shin SK, Lee SK, Lee YC,KimJE, Lee H.AlimentPharmacol Ther. 2013 Sep;38(6):619-­‐27.

TheappendixmayprotectagainstClostridiumdifficilerecurrence.ImGY,Modayil RJ, Lin CT,GeierSJ,Katz DS, FeuermanM,GrendellJH. Clin GastroenterolHepatol. 2011Dec;9(12):1072-­‐7.

Clinicalprac-ceguidelines for Clostridiumdifficileinfec-oninadults:2010updatebythesocietyforhealthcareepidemiologyof America(SHEA)andthe infec-ousdiseasessocietyof America(IDSA).Cohen SH,GerdingDN,JohnsonS,Kelly CP, Loo VG,McDonald LC,Pepin J,Wilcox MH; Society forHealthcare Epidemiology of America; InfecOous Diseases Society of America. Infect ControlHosp Epidemiol. 2010May;31(5):431-­‐55.

rec u rr e n t c d i r c d i
Recurrent CDI(rCDI)
  • CompleteresoluOon of diseasewhileon convenOonal therapy, followed byrecurrencea^ertreatmentstopped
  • PaOents cannotrecover their indigenous gut microbiota following anObioOcexposure
  • KhorutsA,etal. 2010. J. Clin. Gastroenterol. 44:354-­‐360.Chang JY,etal. 2008. J. Infect. Dis. 197:435-­‐438.
  • rCDIpaOents have lowergutmicrobiota diversity,different fromcontrols, but not similar to other CDIpaOents
  • Chang JY,etal. 2008. J. Infect. Dis. 197:435-­‐438.
  • TreatmentopOons forrCDIthat is refractory to standard oral vancomycin therapyarevery limited
slide8

“Stool Transplant”

RestoraOon of thecolonizaOon resistance through fecalmicrobiotatransplantaOon (FMT)

  • EffecOveagainstrecurrent CDI
  • Durable and lasOngengra^ment of the donormicrobiota

AdaptedfromSurawicz,C.M.Nat.RevGastroenterol.Hepatol.10,10-11(2013)

slide9

TheN"EVVENGLAND

JOURNALoflVlEDICINE

JANUARY31,2013

VOL.3&8NO.S

£.:>TABJ..LHEDlN-18_1_,=t

DuodenalInfusionofDonorFecesforRecurrent

Clostridiumdtfficile

Elsv.,nNood,f\.1.D,AnneVrl!!Ze,M.D..MaxNieuwdorp,MD.,PhD,Susan.,Fuentes,Ph.D,

ErwinG.ZoetendalPh.D.,WillemM.deVos,Ph.D.,CarolineE.Visser,M.D.,Ph.D.,EdJ.Kuijper,M.D.,Ph.D.,JoepF.W.M.Bartelsman.M.D.,janGPTijssen,Ph.D.,PeterSpeeman,M.D..PhD.,

MarcelG.W.Dij<graa':Ph.D.•andjosbertJ.Keller.\11-D.,Ph.D.

...showedsignificantlyhighercureratethan

Fecaltransplantationtreatment...

antibiotics

Percentagecuredwithoutrelapse

93.8

Patientswithrecurrent

C.difficileinfection

81.3

Donor-fecesinfusion

Vancomycin

30.8

Assessmentat

10weeksfollowingtreatment

Assessment

10weeksaftertreatment

Firstinfusionofdonorfeces

Infusionof

donorfeces

overall

Vancomycin

chall e n ge s w ith f ec al t r ansplants
Challenges with fecal transplants
  • Risks of transmission of viruses and bacteria thatareyetuncharacterized (even with careful donor screening)
  • Unclear potenOal for longtermcomplicaOons (diabetes,cancer,etc) and difficult to study (each donor and hostwill be different)
  • Unclear sample stability – if fresh, needs to be used within a shortperiod of Ome but unclearexactly how long it is stable
  • “Ick” factor – steps involved to prepare a fecal transplant sampleare“yucky”
  • Difficult to QC “regulate”,given variability between donors andwithin the same donoroverOme
e ve n in a sin g l e d o n o r th e r e is si g ni c an t va r i a o o n o ver o m e
Even in a single donor there is significant variaOon overOme
  • Marked changes observed in therelaOve proporOon of bacteria in the samedonor overOme

>1yr later

  • ComposiOonal “stability” of product overOmeunclear,even from samedonor

1stFMT

2ndFMT

Change inbacterialcomposi-onof fecalsample from the same donor

REF:Braceet al.,J CrohnsColi9s(2014)[Epub ahead of print]

slide13

PotenOal advantages of a definedmicrobial ecosystem

  • ExactcomposiOon of bacteria administered would beknown andcontrolled
  • Mixturecan bereproduced if futuretreatment necessary
  • Longterm outcomes can betracked and measured in a registry and linked back to a specific bacteria composiOon
  • More stable than stool,which must becollected fresh and used within 6hours of collecOon
  • Absence of viruses and other pathogens in the administered mixture(paOent safety)
  • Less unpleasant-­‐ psychological/ sociological sOgma associated with usingstool is eliminated
slide14

METHODOLOGYOpenAccess

I

StoolsubstitutetransplanttherapyfortheeradicationofClostridiumdifficileinfectio,1n:'RePOOPulating'thegut

345

1

Elaine0Petrort,GregoryBGloor2r,StephenJVanner,ScottJWeese,DavidCarter,MichelleCDaigneauk,

EricMBrown5Kathleenxhroete<JndEmmaAllen-Vercoe5

r

e c o s y s tem th e r ap e u o c s
“Ecosystem therapeuOcs”
  • Emerging paradigm in medicine
  • Displacing a damaged ecosystemwith a healthy ecosystem(e.g. fecal transplantaOon)
  • How do we define a healthyecosystem?
    • Encodes a full funcOonal repertoireof genes
    • Can exist in a stableequilibrium
    • Colonizes and persists
  • Contrastwith tradiOonal probioOcs
    • Have to betaken conOnuously to bemaintained
slide17

Our approach:

createadefinedspeciesfecaltransplant

Cultureincontrolledenvironment

Infuseinto patientvia rectum

Donor sample

Remove pathogens

GOAL:

Consistent,scalable(?),andreliablewiththesameresultsasa fecaltransplant(FMT)

slide18

Bacteria with potenOal risks wereeliminated

Example

Criteria

Knownpathogensbasedonstrain

Bacteroides fragilis

Coprococcus comes:resistant to mulOpleanObioOcs tested

Riskofantibiotic resistance

E.coli:chose to include more suscepOble strain

Uncertainrisk

rep oo pul ate rp
“RePoopulate” (RP)
  • 33 strains
  • Communitytested forecosystem stabilityin the Robogut
  • EsOmated concentraOon of 3.5 x109 CFU/ mL
  • 100mL total vol. administered, pre-­‐reduced (anaerobic)
  • Used within 24 hours of preparaOon
  • Oral vancomycin held 48hrs prior totreatment
  • Administered bycolonoscopy

Petrofetal.,Microbiome(2013),1:3

slide20

“Synthe-c”stoolinfusionpreventsaddi-onal CDI episodes inpa-entswith recurrent

C.difficileinfec-on(CDI)

Petrofetal.,Microbiome(2013),1:3

slide21

PaOentmicrobiotaremodels overOme to acompositeof RP and paOentmicrobiota

  • Both paOents sOll symptom-­‐freeat6-­‐month followup
  • 25%of RePOOPulatestrains retained at6 months in paOent1
  • 36%of RePOOPulatestrains retained at6 months in paOent2

Patient2

Patient1

RP = RePOOPulate (syntheOc stool)M6 = Month 6

PT = Pre-­‐transplant

REF:Petrofetal.,Microbiome(2013),1:3

slide22

Challenges of a defined microbial ecosystem

  • Difficult-­‐to-­‐grow bacteria makes large-­‐volume commercial scale-­‐up a challenge
  • Cost: need highly skilled personnel to runin vitrocultureequipment;expensive to produce (stool ischeap)
  • QC and regulaOon of complex microbialecosystems is a new, ill-­‐defined area (different from probioOcs)
su mm a r y
Summary
  • It is possible to create a therapeuOcmicrobialecosystem to treatC.difficileinfecOons
    • may be a feasible alternaOve to “convenOonal” stooltransplants
  • Probablymore “safe” -­‐certainlymorereproducible-­‐than convenOonal FMT
  • Moreresearch needed in this area
    • decreased diversitymay be less important than theactualorganisms in themixture, and theirmetabolites
    • ?QC and diagnosOcs
    • ?applicaOons in other disease states (obesity,IBD,etc)
ac k n o w l e d g eme n ts
Acknowledgements
  • Queen’s University
  • Petrof lab:
  • -­‐ ChantalleBrace
  • -­‐ Dr. JulieMcDonald
  • -­‐ Shu-­‐Mei He
  • -­‐ CurOsNoordhof
  • -­‐ Dr. Teklu Gerbaba
  • PaOentcare:
  • Dr. Stephen Vanner
  • Dr. Mark Ropeleski
  • Dr. Lawrence Hookey
  • Dr. Gerald Evans
  • Dr. Chris Smith
  • UniversityofColorado
  • Dr. Daniel Frank

UniversityofGuelph

Dr. Emma Allen-­‐Vercoe & lab

Dr. Sco[Weese

UniversityofWesternOntario

Dr. GregGloor Dr. GregorReid

Funded by: