Post on 17-Oct-2020
TheLeading-EdgeofEffectiveSurgicalProphylaxis
SherylZelenitskyProfessor,CollegeofPharmacy
UniversityofManitoba
http://creativecommons.org/licenses/by-sa/4.0(WikimediaCommons)
■ Ihavenocurrentorpastrela0onshipswithcommercialen00es,andwilldonatethecurrent$200speakinghonorariumtotheCSHPFounda0on.
■ Thisprogramlearningac0vityhasreceivednofinancialorin-kindsupportfromanycommercialorotherorganiza0on
Disclosures
AcknowledgementsDivnaCalic,PhDcandidate
ChrisLawson,BSc(Pharm)
RyanLillico,PhDcandidate
Dr.TedLakowski,Professor
Dr.G.Zhanel,Professor
Dr.RakeshAurora,CardiacSurgery
Dr.RobAriano,Pharmacy
Dr.HilaryGrocoQ,Anesthesiology
http://cibinel.com/project/apotex-centre/
https://markosun.files.wordpress.com/2015/05/aerialspov22.jpg
Outline
1. Surgicalsiteinfec0ons(SSIs)andan0microbialprophylaxis(AP)
2. Limita0onsofgold-standardtrials,meta-analyses&clinicalprac0ceguidelines
3. Whatis“effec0ve”AP?Studiesincolorectalandcardiacsurgery
4. Howtoop0mizeAPforpa0entsintheclinicalse\ng?
LearningObjective
1. Tolearnhowan0microbialpharmacodynamicscontributetoeffec0vesurgicalprophylaxis;
2. Toiden0fytheprimaryvariablesinassessingan0microbialprophylaxis.
- 2-5%ofsurgeries
- ↑hospitalstay7-10d,re-admission5X
- ↑mortality2-3X
- $350,000-$1millionannually
SSIhealthcareburden
KnoopKJ,StackLB,StorrowAB,ThurmanR.TheAtlasofEmergencyMedicine,4e;2016http://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=125437734,AccessedFeb19,2017
https://www.swchildrens.org/Pages/health-safety/health-library/library-detail.aspx?docId=%7B0A696E96-7165-456D-AAAA-D8E2A9851EA5%7D,AccessedFeb19,2017
- 50%ofSSIsarepreventable
TableII.6.7(WHO:PatientSafety:GuidelinesforSafeSurgery2009)
ü modifiablepa0entrisk-factors
ü skinprepara0on,ORinfec0oncontrol,surgicaltechnique
ü thermoregula0on,glucosecontrol,O2supplementa0on
SSIprevention
Pa0entrisk-factors:• obesity• malnutri0on• smoking• diabetes• ISmeds• coloniza0on• remoteinfec0on
Surgeryrisk-factors:• OR/surgicalcontamina0on• typeofsurgery• foreigndevice• drains• dura0onofsurgery
ü an0microbialprophylaxis
- reducebacterialburdenatincisionsiteandpreventSSI
- avoidSSI-associatedmorbidity,mortality&costs
- minimizecollateralresistance(eg,MRSA,ESBL,VRE)
- avoidan0microbial-relatedadverseeffects(eg,C.difficile)
GoalsofAPareto…
? selec0ngan0microbial
? selec0ngdose
? 0mingpre-opdose(within1h)
? re-dosingduringsurgery(every2t½’s)
? con0nuingajersurgery(none,<24hor48hforcardiacsurgery)
KeyAPdecisionsare…
APclinicalpracticeguidelines(CPGs)
2013
Limitationsofgold-standardtrials,meta-analyses&CPGs
- heterogeneouspa0ents… age,weight,Clcr,co-morbidi0es
- variablesurgeries… skinprep,ORinfec0oncontrol,dura0onofsurgery
- diverseSSIpathogens… hostnormalflora,localpathogendistribu0ons
- variousan0microbials… spectrumofac0vity,resistancerates,PKs
What is “effective” AP?
APforcolorectalsurgery…
Single-dose was more effective than multiple-dose gentamicin.
Incision conc
AUCsurg
Closure conc
Single-dose was more effective than multiple-dose gentamicin.
Gentamicin closure conc was strongest risk-factor for SSI.
Critical threshold = 1.6 mg/L
Gentamicin closure conc was strongest risk-factor for SSI.
APforcardiacsurgery…
Image:BaronS(2013).CardiovascularTherapeutics14:214-239.
n=55,40inPDanalysis69%male65±10y(36–82y)
90±17kgClcr74±16mL/min
⇒ SSIs at 30 days
X
X
X Incision conc
Closure conc
Istherecommendedcefazolinprophylaxisadequateincardiacsurgery?
₋ sex
₋ age
₋ weight
₋ BMI
₋ smoker
₋ Clcr
₋ diabetes
₋ Charlsonindex
₋ priorcardiacsurgery
₋ antibiotics<1month
₋ hospitalized<1month
₋ CABG,valvesurgery
₋ #grafts
₋ albumin
₋ glucose
₋ fluidbalance
₋ bloodreplacement
₋ CPBduration
₋ surgeryduration
₋ complications
₋ hospitalstay
₋ pre-opAPonly
₋ timingofpre-opAP
₋ cefazolindose
₋ totalcefazolindose
₋ cefazolinclosureconc
₋ cefazolinminconc
Cefazolin closure conc & duration of surgery were associated with SSI.
Zelenitskyetal.IDWeek2016,NewOrleans,NO.
Variable OR 95%CI p-value Cefazolinclosureconc(per10%decrease) 1.36 1.02-1.82 0.038
Durationofsurgery(per1hincrease) 2.94 1.13-7.64 0.027
AreaundertheROCcurve(95%CI)=0.789(0.583-0.996)Hosmer-Lemeshowp-value=0.21
T50 3.9 h
T25
T75
Critical threshold = 104 mg/L
₋ sex
₋ age
₋ weight
₋ BMI
₋ smoker
₋ Clcr
₋ diabetes
₋ Charlsonindex
₋ priorcardiacsurgery
₋ antibiotics<1month
₋ hospitalized<1month
₋ CABG,valvesurgery
₋ #grafts
₋ albumin
₋ glucose
₋ fluidbalance
₋ bloodreplacement
₋ CPBduration
₋ surgeryduration
₋ complications
₋ hospitalstay
₋ pre-opAPonly
₋ timingofpre-opAP
₋ cefazolindose
₋ totalcefazolindose
₋ cefazolinclosureconc
₋ cefazolinminconc
Variable OR 95%CI p-value Cefazolinclosureconc(per10%decrease) 1.36 1.02-1.82 0.038
Durationofsurgery(per1hincrease) 2.94 1.13-7.64 0.027
AreaundertheROCcurve(95%CI)=0.789(0.583-0.996)Hosmer-Lemeshowp-value=0.21
Zelenitskyetal.IDWeek2016,NewOrleans,NO.
Cefazolin closure conc & duration of surgery were associated with SSI.
“Thus,themost importantaspect inthe7minganddosingofprophylac7can7bio7csisachievingeffec7velevelsthroughoutthe7methattheincisionisopen.”
“Thus…toprovideserumand7ssueconcsexceedingtheMICsformostprobableorganisms…atthe7meof incision,andforthedura7onoftheprocedure.”
What is “effective” AP?
How can this optimize AP for patients in the clinical setting?
Bratzleretal.AmJHealth-SystPharm2013;70:195-283.
30 40 50 60 70 80 90AGE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0 50 100 150WT
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Proportion per B
ar
0
100
200
300
400
500
600
700
800C
ount
50 60 70 80 90 100 110 120 130CLCR
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20VDL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0 5 10 15 20 25VD
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Proportion per B
ar
0
100
200
300
400
500
600
700
Cou
nt
1.0 1.5 2.0 2.5 3.0T12
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0.2 0.3 0.4 0.5KE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
1 2 3 4 5 6 7 8 9CL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10CLKG
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20F
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
100 200 300 400FD
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
10 20 30 40 50 60 70CP
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Proportion per B
ar0
100
200
300
400
500
600
Cou
nt
30 40 50 60 70 80 90AGE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0 50 100 150WT
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Proportion per B
ar
0
100
200
300
400
500
600
700
800
Cou
nt
50 60 70 80 90 100 110 120 130CLCR
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20VDL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0 5 10 15 20 25VD
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Proportion per B
ar
0
100
200
300
400
500
600
700
Cou
nt
1.0 1.5 2.0 2.5 3.0T12
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0.2 0.3 0.4 0.5KE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
1 2 3 4 5 6 7 8 9CL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10CLKG
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20F
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
100 200 300 400FD
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
10 20 30 40 50 60 70CP
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Proportion per B
ar
0
100
200
300
400
500
600
Cou
nt
30 40 50 60 70 80 90AGE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0 50 100 150WT
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Proportion per B
ar
0
100
200
300
400
500
600
700
800
Cou
nt
50 60 70 80 90 100 110 120 130CLCR
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20VDL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0 5 10 15 20 25VD
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Proportion per B
ar
0
100
200
300
400
500
600
700
Cou
nt
1.0 1.5 2.0 2.5 3.0T12
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0.2 0.3 0.4 0.5KE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
1 2 3 4 5 6 7 8 9CL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10
CLKG
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20F
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
100 200 300 400FD
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
10 20 30 40 50 60 70CP
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Proportion per B
ar
0
100
200
300
400
500
600
Cou
nt
E.coli32%
MSSA15%
MRSA4%
P.aeruginosa10%
Klebsiellaspp9%
Streptococcusspp9%
S.epidermidis9%
Enterobacterspp8%
Proteusspp4%
30 40 50 60 70 80 90AGE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0 50 100 150WT
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Proportion per B
ar
0
100
200
300
400
500
600
700
800
Cou
nt
50 60 70 80 90 100 110 120 130CLCR
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20VDL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0 5 10 15 20 25VD
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Proportion per B
ar
0
100
200
300
400
500
600
700
Cou
nt
1.0 1.5 2.0 2.5 3.0T12
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar0
100
200
300
400
Cou
nt
0.2 0.3 0.4 0.5KE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
1 2 3 4 5 6 7 8 9CL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10CLKG
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20F
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
100 200 300 400FD
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
10 20 30 40 50 60 70CP
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Proportion per B
ar
0
100
200
300
400
500
600
Cou
nt
30 40 50 60 70 80 90AGE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0 50 100 150WT
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Proportion per B
ar
0
100
200
300
400
500
600
700
800
Cou
nt
50 60 70 80 90 100 110 120 130CLCR
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20VDL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0 5 10 15 20 25VD
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Proportion per B
ar
0
100
200
300
400
500
600
700
Cou
nt
1.0 1.5 2.0 2.5 3.0T12
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
0.2 0.3 0.4 0.5KE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
1 2 3 4 5 6 7 8 9CL
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10CLKG
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Proportion per B
ar
0
100
200
300
400
500
Cou
nt
0.05 0.10 0.15 0.20F
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
100 200 300 400FD
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Proportion per B
ar
0
100
200
300
400
Cou
nt
10 20 30 40 50 60 70CP
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Proportion per B
ar
0
100
200
300
400
500
600
Cou
nt
%ofcaseswhereAPcoversprobableSSIpathogens
duringsurgery
MCSn=5,000
Pa0entdemographics–age,wt,Clcr An0microbialPKs–Vd,t½,%free
SSIpathogen,MICdistribu0onsSurgerydura0on
Zelenitskyetal.JAC2016;;71:2902-8.
MonteCarlosimulation(MCS)modelling
Zelenitskyetal.JAC2016;71:2902-8.
Ertapenem1g
Cejriaxone2gGentamicin5mg/kgLevofloxacin500mg
Cefazolin2gCefoxi0n2g
%ofcaseswhereAPcoversallprobableaerobicSSIpathogens
Metronidazole500mgErtapenem1g
Clindamycin900mgCefoxi0n2g
Zelenitskyetal.JAC2016;71:2902-8.
%ofcaseswhereAPcoversallprobableanerobicSSIpathogens
5mg/kg
S.aureusOtherEnterobacteriaceaeE.coliAllSSIaerobes
3mg/kg 1.5mg/kg
Zelenitskyetal.JAC2016;;71:2902-8.
%ofcaseswheregentamicincoversallprobableaerobicSSIpathogens
OtherAPquestions…
“Thus, themost important… is achieving effec7ve levels throughout the7methattheincisionisopen.”(WHOGlobalguidelinesforthepreven0onofSSI2016)
? selec0ngan0microbial
? selec0ngdose
? 0mingpre-opdose
? re-dosingduringsurgery
? con0nuingajersurgery
- Whentousecejriaxoneinsteadofcefazolinincolorectalsurgery?- ShouldazithromycinbeaddedtocefazolininC-sec0ons?(Titaetal,NEJM2016)
- Howtodosecefazolininobesepa0entsie,3gfor>120kg?
Today’s Hospital 2005 – “Why timing is everything with AP and surgery” Medscape ID 2013 – “Surgical AP: Timing doesn’t alter risk”
- Howtoconsiderrenalfunc0oninre-dosing?- Shouldcon0nuousinfusioncefazolinbeusedincardiacsurgery?
Selectreferences(recentprac0ceguidelines,reviewsandresources):
§ Andersonetal.Strategiestopreventsurgicalsiteinfec0onsinacutecarehospitals:2014update.InfectControlHospEpidem2014;34(6):605.
§ Banetal.AmericanCollegeofSurgeonsandSurgicalInfec0onSociety:Surgicalsiteinfec0onguidelines,2016update.JAmCollSurg2017;224(1):59.
§ Bratzleretal.Clinicalprac0ceguidelinesforan0microbialprophylaxisinsurgery.AmJHealth-SystPharm2013;70(3);195.
§ Bronwenetal.Surgicalsiteinfec0ons:anupdate.InfectDisClinNAm2016;30:909.
§ CanadianPa0entSafetyIns0tute:SurgicalSiteInfec0ons(Ge\ngStartedKit)(hQp://www.pa0entsafetyins0tute.ca/en/Topic/Pages/Surgical-Site-Infec0on-(SSI).aspx);(hQp://www.pa0entsafetyins0tute.ca/en/toolsresources/pages/ssi-resources-ge\ng-started-kit.aspx)
§ Najjaretal.Prophylac0can0bio0csandpreven0onofsurgicalsiteinfec0ons.SurgClinNAm2015;95:269.
§ WHOGlobalguidelinesforthepreven0onofsurgicalsiteinfec0on2016(hQp://www.who.int/gpsc/ssi-guidelines/en/)
§ WHOGuidelinesforSafeSurgery2009.(hQp://www.who.int/pa0entsafety/safesurgery/tools_resources/9789241598552/en/)
Thankyou!Questions?