an#bio#c stewardship as part of the prevenon...

An#bio#cstewardshipaspartofthepreven#onstrategyDrDavidRJenkinsConsultantMedicalMicrobiologistUniversityHospitalsofLeicesterNHSTrust,HonoraryReader,[email protected]

@DafyddSiencyns

THEEVOLUTIONOFRESISTANCEISDRIVENBYANTIBACTERIALS

Achronologyfortheemergenceofresistance

Date antibiotic introduced into clinical practice Date antibiotic resistance identified 1940 penicillin resistant Staphylococcus

penicillin 1943 tetracyclines 1948 erythromycin 1952 vancomycin 1958

1959 tetracycline resistant Shigella methicillin 1960

1962 methicillin resistant Staphylococcus aureus (MRSA) 1965 penicillin resistant Streptococcus pneumoniae 1968 erythromycin resistant Streptococcus

gentamicin 1971 1979 gentamicin high level resistant Enterococcus

imipenem, ceftazidime 1985 1987 ceftazidime resistant Enterobacteriaceae 1988 vancomycin resistant Enterococcus

levofloxacin 1996 levofloxacin resistant Streptococcus pneumoniae 1998 imipenem resistant Enterobacteriaceae

linezolid 2000 XDR tuberculosis 2001 linezolid resistant Staphylococcus 2002 vancomycin resistant Staphylococcus

daptomycin 2003 2004 PDR Acinetobacter and Pseudomonas 2009 ceftriaxone resistant Neisseria gonorrhoeae, PDR Enterobacteriaceae

ceftaroline 2010 2011 ceftaroline resistant Staphylococcus

AdaptedfromCDC,An6bio6cresistancethreatsintheUnitedStates,2013,

ANTIBACTERIALRESISTANCEACCUMULATES

G28 SUM3 Collect.:12/06/2012 Recd.:12/06/2012 N , 6286222308 S0357918

Specimen No : MG043114Y Microbiology <PgUp/PgDn> for more ──────────────────────────────────────────────── ref lab no H1 2250 0354 Further report Klebsiella pneumoniae subsp. pneumoniae We confirm this isolate as pan-resistant and do not find any available sensitivities. The key features of an NDM-carrying isolate are pan-cephalosporin- / carbapenem- / aminoglycoside-resistances with significant potentiation of Imipenem by EDTA.

Resistance to Aztreonam suggests underlying ESBL and possibly AmpC activity, as these determinants are often co-located with b1aNDM.

Antibiotic MIC (mg/L) S/I/R Breakpoint (mg/L) Amikacin >64 R 8 & 16 Gentamicin >32 R 2 & 4 Tobramycin >32 R 2 & 4 Amoxicillin/ Clavulanate >64 R 8 Ampicillin >64 R 8 Aztreonam >64 R Cefotaxime >256 R 1 & 2 Cefotaxime/ clav-ESBL test >32 X Cefoxitin >64 R 8 Cefpirome >64 R 1 Ceftazidime >256 R 1 & 8 Ceftazidime/ Clav-ESBL test >32 X Ertapenem >16 R 0.5 & 1 Imipenem 128 R 2 & 8 Imipenem/ EDTA-MBL test 1 X Meropenem >32 R 2 & 8 Piperacillin >64 R 16 Piperacillin >64 R 16 Sulbactam >32 R Temocillin >128 R Cefpirome/Clav >32 X Cefotaxime/ cloxacillin >256 X Colistin >32 R 2 Ciprofloxacin >8 R 0.5 & 1 Minocycline 32 R Tigecylcine 4 R 1 & 2 Fosfomycin 64 R Rifampicin >32 R

ANTIBACTERIALUSESELECTSFORANTIBACTERIALRESISTANCE

Resistantbacteriainprimarycarefollowingan#bacterialtreatmentSystema#creviewandmeta-analysisofrela#onshipbetweenprioran#bacterialexposureandresistanceinindividualpa#entsinprimarycare

•  24studies•  An6bio6csforurinarytractorrespiratorytractinfec6ons

linkedwithincreasedratesofcarriageofresistantbacteriainrecipientpa6entsforupto12months(pooledoddsra6o=2.5at2monthspostan6bio6cs)

•  Longerdura6onsandmul6plecoursesassociatedwithhigherresistancerates

CostelloeCetal.Bri6shMedicalJournal2010;340:c2096

ANTIBACTERIALRESISTANCECOSTSLIVESANDHEALTHCARERESOURCES

EuropeanUnionpopula6on500m25,000deathsperyear2.5mextrahospitaldaysOverallsocietalcosts(€900million,hosp.days)Approx.€1.5billionperyear

Es#matesofburdenofan#bacterialresistance

UnitedStatespopula6on300m>23,000deathsperyear>2.0millnessesOverallsocietalcostsUpto$20billiondirectUpto$35billionindirect

Thailandpopula6on70m>38,000deaths>3.2mhospitaldaysOverallsocietalcostsUS$84.6–202.8millionDirect>US$1.3billionindirect

AdaptedfromWorldHealthOrganisa6on,An6microbialresistance:globalreportonsurveillance(2014)

Study:Retrospec6vecohortstudyofassocia6onbetweenan6bio6cregimenandsurvivalto30daysa]erdiagnosisofKPC-producingKlebsiellapneumoniaebacteraemiaSeang:ThreelargeItalianteachinghospitals

an#bio#cregimen

Mortalityoddsra#o(95%CI)

monotherapy 1.59(1.06-2.38)

2-drugcombina6on

0.97(0.64-1.48)

3-drugcombina6on

0.36(0.15-0.92)

Combina6ontherapywith6gecycline,colis6nandmeropenem

TumbarelloMetal.ClinInfectDis.2012;55:943-50

An#bio#ctreatmentofKPC-producingKlebsiellapneumoniaebacteraemia

THEREAREFEWNEWANTIBACTERIALS

SilverLL.ClinMicrobiolRev2011;24:71-109

Thediscoveryvoid

An#bacterialscurrentlyinphase1-3ofdevelopment

Gramposi6veprioritypathogens:16products,including2newan6bio6cclassesand7biologicalagents(monoclonalan6bodiesandendolysins)Gramnega6veprioritypathogens:Almostallproductsaremodifica6onsofexis6ngclasses,ac6veagainstlimitedrangeofbacteria

An6bacterialagentsinclinicaldevelopment:ananalysisofthean6bacterialclinicaldevelopmentpipeline,includingtuberculosis.WHO,2017

AREWERUNNINGOUTOFEFFECTIVEANTIBACTERIALDOSES?

Effec6vean6bacterialdoses

1941

Peakan6bacterialefficacy

?Time(years)

Eraofan6bacterialdiscovery

Hastheworldpassedpeakan#microbialefficacy?

Post-an6bio6cera

X Now?

ISANTIBACTERIALSTEWARDSHIPTHEANSWER?

IDSAdescrip#onofan#microbialstewardship

•  Coordinatedinterven6onsdesignedtoimproveandmeasurethe

appropriateuseofan6microbialsbypromo6ngtheselec6onofthe

op6malan6microbialdrugregimen,dose,dura6onoftherapy,androute

ofadministra6on.An6microbialstewardsseektoachieveop6malclinical

outcomesrelatedtoan6microbialuse,minimizetoxicityandother

adverseevents,reducethecostsofhealthcareforinfec6ons,andlimit

theselec6onforan6microbialresistantstrains.

Thegrowthofinterestinan#microbialstewardship–PubMedcita#ons

DyarOJetal.ClinicalMicrobiologyandInfec6on2017,inpress

An#microbialstewardshipandregula#oninhumanhealth

h`p://www.who.int/an#microbial-resistance/global-ac#on-plan/database/en/

Stewardshipinterven#ontypes•  Persuasive

§  Educa6on§  Consensus§  Opinionleaders

§  Reminders§  Audit§  Feedback

•  Restric#ve§  Restricted

suscep6bilityrepor6ng

§  Formularyrestric6on

§  Priorauthorisa6on

§  Automa6cstoporders

•  Structural§  Computerised

records§  Rapidlab

tests§  Expert

systems§  Quality

monitoring

DaveyPetal.CochraneDatabaseofSystema6cReviews2013

221studies: 58randomisedcontrolledtrials,163non-randomisedstudies NorthAmerica 96 Europe 87 Asia 19 SouthAmerica 8 Australia 8 EastAsia 3

Outcome Absoluteeffect

Withoutinterven6on Withinterven6on

%ofpa6entstreatedaccordingtoan6bio6cprescribingguidelines

43% 58%

Dura6onofan6bio6ctherapy 11.0days 9.1days

Mortality 11% 11%

Lengthofhospitalstay 12.9days 11.8days

DaveyPetal.Interven6onstoimprovean6bio6cprescribingprac6cesforhospitalinpa6ents.CochraneDatabaseofSystema6cReviews.2017;2.

ANEXAMPLEOFANTIBACTERIALSTEWARDSHIPAIMEDATREDUCINGRESISTANCE

Changingprescribingprac#cethrougheduca#ontotackleanESBL-Klebsiellapneumoniaeoutbreak

•  HospitalclonaloutbreakofESBL-producingK.pneumoniae(ESBL-KP)

•  Educa6onalan6bio6cinterven6on–  Primaryaim:reduce

prescrip6onsofsecondandthird-genera6oncephalosporins

–  Secondaryaim:avoidincreasedconsump6onoffluoroquinolonesandcarbapenems.

TangdenTetal.JAn6microbChemother2011;66:1161-1167

Newtreatmentprotocolstoreplacecephalosporins

Diagnosis Recommendedan6bio6ctreatment

Abdominalinfec6ons Piperacillin/tazobactam

Community-acquiredpneumonia

PenicillinG(+moxifloxacinifsep6c)

Hospital-acquiredpneumonia

Piperacillin/tazobactam

Febrileurinarytractinfec6on

Piperacillin/tazobactamorcefotaxime

Sep6cshock Imipenemormeropenem

Severesepsisinpa6entswithknownESBLcarriage

Imipenemormeropenem

Changingprescribingprac#cethrougheduca#ontotackleanESBL-Klebsiellapneumoniaeoutbreak

TangdenTetal.JAn6microbChemother2011;66:1161-1167

...thecausaleffectofthean#bio#cinterven#onisdifficulttoevaluatebecauseofanunknownnaturalcourseoftheoutbreakandothersimultaneousac#ons,includinghygienicmeasures

However…

MicrobialoutcomesofAMSprogrammes

•  26interrupted6meseriesstudies– prescribingoutcomesat6monthsandmicrobialoutcomes(AMR,CDI)at12monthspost-interven6on

•  20plannedinterven6ons•  6unplannedinterven6ons

–  respondingtooutbreaks– associatedwithgreatereffectsonmicrobialoutcomesthanplannedinterven#ons


•  Uncertaintyabouttheeffectsofinterven6onsonresistantgram-nega6veandgram-posi6vebacteria


ImpactofAMSinterven#onsonmicrobialoutcomes

(Clostridiumdifficile,MDR-GPC,MDR-GNB)


Indicatesreduc6onintargetmicrobialoutcomesstudied

WHYISITDIFFICULTTOSHOWTHATANTIMICROBIALSTEWARDSHIPREDUCESRESISTANCE?

Whyisitdifficulttoshowthatan#microbialstewardshipreducesresistance?

Possibletechnicalexplana#ons•  Varianceobscuredbenefits•  Toofewpre-interven6on

datapoints•  Inappropriateselec6onof

prescribingoutcomeswhenmorethanonereported

•  Choiceofprescribingandmicrobialoutcomes6mepointspossiblyinappropriate

Possiblesystemicexplana#ons•  AMSprogrammesneedto

bemoreeffec6ve–  15%averageincreaseinadherencetomean58%isinsufficienttodelivermicrobialeffect?

•  “Wrong”choiceofinterven6ons

•  AMSineffec6ve,atleastbyitself

IMPROVINGEFFECTIVENESSOFAMSPROGRAMMES–ENGAGINGCLINICIANS

Whatdocliniciansthinkaboutstewardship?

•  Percep6onsofstewardship:–  AMSasachallengetoclinicalspecialty-specificownership

–  AMSasachallengetoestablishedhierarchiesandconsulta6one6quewe

–  BarrierstonursingrolesinAMS

–  Interspecialtyandinterprofessionaldynamics

•  UnsolicitedAMSadvice,invadingclinicalterritory.

•  “Icanusuallyfixpneumoniawithoutanyinputfromthem.MyfeelingjustisthatIDunderstandbugsvery,verywell,buttheydon’tunderstandlungsverywell.”

IndepthinterviewswithrespiratorydoctorsandnursesinAustralia

BroomJetal.JHospInfect2017;96:316-322



–  AMSasachallengetoestablishedhierarchiesandconsulta#one#que`e



•  Whenapprovalprocessesinvolvedseniorrespiratorydoctorsreques6ngan6bio6capprovalfromamorejuniorAMSdoctor,theprocesswasviewedasinsul6ng.

•  “[AMS]..isrude...offensive...sugges6ngwe’reincompetentandthatwehavenoexper6se”








•  Somenursesunawarewhattheterm“an6microbialstewardship”meant.

•  Fearofadverseclinicaloutcomes,legalimplica6ons

•  “Withholdingthatan6bio6c”...”It’snotsomethingIwanttoriskmyregistra6onfor”.








•  Juniormedicalpar6cipants“caughtinthemiddle”betweentheirownrespiratoryteamandtheAMSteam.

•  “Pharmacywillonlydispenseonedoseiftheapprovalisnotputin.”

•  “We’regeangpressurefromthemedicalteamandwe’rejustpushingitontothepharmacist”



An#microbialprescribingismorethanchoosingtherightdrugattherightdoseattheright#me

“...inthecaseofan6microbialprescribing,prescribinge6queweisakeydeterminantofbehaviour,withprescribingdecisionsinfluencednotonlybyclinicalandtherapeu6cgoalsbutalsobyahostofculturaldeterminantsandclinicalgroupsacrossdifferentspecial6es.”

CharaniEetal.ClinicalInfec6ousDiseases2013;57:188–96

AMSNEEDSANUNDERLYINGTHEORYTOEXPLAINANDPREDICTPRESCRIBINGBEHAVIOUR

Principal-Agenttheory

PRINCIPAL AGENT

CONTRACT

• Howtoensureagentsperforminthewayprincipalsexpectthemto.(Adverseselec6on)• Howtoaligntheconflic6nggoalsofprincipalsandagents.(Moralhazard)Problemsarisewhenitisdifficultorexpensivefortheprincipaltoverifywhattheagentisdoing

KMEisenhardtAcadManagementRev1989;14:57-74

AMSprogramme An6bio6cprescriber

AMSISMORETHANABOUTANTIBACTERIALPRESCRIBING

Stewardshipactorsandac#ons


22elementsofresponsiblean#bio#cuse

hwp://drive-ab.eu/wp-content/uploads/2015/06/Defini6on_RU_07042017final.pdf

CANYOUBELIEVETHESENSITIVITYRESULTSFROMYOURMICROBIOLOGYLABORATORY?

Varia#oninan#bacterialdiscquality

See:KahlmeterG.ClinMicrobiolInfect2016;22:211-212

“Theresults,somegood,someappalling...”

DOYOURANTIBIOTICSWORK?

An#bacterialquality:co-trimoxazolefromGhana,NigeriaandUnitedKingdomCountryofpurchase

Numberofsamples

MiniLab HPLCcontentanalysisadherence

Dissolu#ontestcompliancecolorimetric

testThin-layerchromatography

Ghana(1samplemadeinIndia)

5 5/5pass 4/5pass 0/5pass 2/5pass

Nigeria 9 9/9 8/9 0/9 3/9

UnitedKingdom

1 1/1 1/1 1/1 1/1

FadeyiIetal.AmJTropMedHyg.2015;92(suppl6):87-94

Theroleofinfec#onpreven#onandcontrolinAMS

Abroaderviewofstewardship

•  Oversightandguidanceofasystem•  Ensuringstrategicpolicyframeworksexist,combinedwitheffec6veoversight

•  Coali6on–building•  Regula6on•  Awen6ontosystem-design•  Accountability

WiysongeCSetal.Publicstewardshipofprivatefor-profithealthcareprovidersinlowandmiddle-incomecountries.CochraneDatabaseofSystema6cReviews2016,8.

Astrategicapproachtostewardship

•  Acoherentsetofac6onsdesignedtousean6microbialsresponsibly– Rangesfromindividuallevelac6onstoglobalac6ons

– Notrestrictedtowri6ngprescrip6ons


Conclusions

•  AMSisnotyetproventobeaneffec6vestrategytocounterchallengeofresistance

•  Founda6onalAMStheoryisrequiredtosupporteffec6venessofinterven6ons

•  Greaterunderstandingneededofop6malinterven6ons

•  AMSshouldbemorethanaboutprescribersandprescribing

an#bio#c stewardship as part of the prevenon...

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