JustificationandProtocolforExtended‐InfusionPiperacillin/Tazobactam
inAdultPatients
version2/5/13[DRAFT]
EXECUTIVESUMMARY
1.
Useofextendedinfusions(EI)ofpiperacillin‐tazobactam(PTZ)optimizestheprobabilitythatdrug
concentrations will remain above the minimum inhibitory concentration (MIC) for an appropriate
periodoftime.
2. ThegoalsoftheextendedinfusionPTZprotocolaretooptimizetreatmentoutcomes,whilecurtailing
resistancetoPTZandreducingcost.
3. We recommend implementing the extended infusion protocol in all adult patients to realize
both clinical and economic advantages. It was noted that a number of Pseudomonas aeruginosa
isolatesat<<HOSPITAL>>haveMICs>8mcg/mLandtheextendedinfusionprotocolwouldofferan
advantageinthetreatmentofthesecases.
BACKGROUND
Piperacillin/tazobactam is a β‐lactam/ β‐lactamase inhibitor combination formulary antibiotic frequently
usedatXXXHospitalforthetreatmentofmoderate‐to‐severeinfections,includingsepsis,lowerrespiratory
tract, urinary tract, complicated skin and skin structure, gynecologic, bone and joint, and intra‐abdominal
infections.Overall,PTZisoneofthemostcommonlyusedantibioticsat<<HOSPITAL>>.
Increasing antimicrobial resistance and the resulting increased mortality has led to the reevaluation of the
optimal method to administer antibiotics. Studies have shown that for β‐lactams (including PTZ), the best
predictor of bacterial killing is the time during which the free drug concentration exceeds the minimum
inhibitory concentration of the organism (%fT>MIC). Specifically, maximal bactericidal effect is achieved
when free drug concentration exceeds the MIC by approximately four‐fold for 40% to 60% of the dosing
interval.1,2
JUSTIFICATION
Pharmacodynamic studies. Several studies have explored the PK/PD parameters of PTZ with the goal of
optimizing its clinical utility. These studies have focused on strategies to enhance the duration of drug
exposure.Inonesuchstudy(illustratedinFigure1),theprobabilitiesoftargetattainmentof50%fT>MIC
forPTZwereasfollows:
 3.375gq6hr(0.5‐hrinfusion):>90%forMICvalues≤1mg/L
 3.375gq4hr(0.5‐hrinfusion):>90%forMICvaluesupto8mg/L
 3.375gq8h(4‐hrinfusion):>90%forMICsupto16mg/L
1 Figure1:P
Probabilitieso
oftargetattain
nmentwithPT
TZ4
MIC = minimum
m inhibitory conce
entration
ptofourtimessdaily)failedtoprovidead
dequatetime above
Asillustraatedabove,traaditionaldosingofPTZ(up
theMICfo
ororganismsw
withanMIC>8mg/L.3,4No
oneofthereg imenswerereeliableatanM
MICof64mg//L(the
susceptibiilitybreakpoin
nt).Alternativ
vely,adoseoff3.375gq8hr infusedover 4hoursproviidesaprobabiilityof
target atttainment >90% for an MIIC up to 16 mg/L at a loower total d aily dose thaan standard doses.
Furthermo
ore,PTZlackssanypersisten
nteffects(posst‐antibioticeeffect)thatlasstafterantimicrobialexposureto
mostorgaanisms,suchth
hatoncetheffreedrugconccentrationsfalllbelowtheM
MIC,bacterialrre‐growthisaalmost
instantaneeous. Extend
ding the admiinistration tim
me takes advaantage of the pharmacodyn
namic propertties of
thisextendedspectrum
mβ‐lactam/β‐lactamaseinhiibitorcombinaation.
t MICs of PTZ
P
against P.
P aeruginosa isolates was conducted w
with <<HOSPIT
TAL>>
An internal review of the
ogy data from
m January 201
11 to Decemb
ber 2011. Acccording to th
he Clinical Lab
boratory Stan
ndards
microbiolo
Institute (CLSI)
(
guideliines, the breaakpoint for su
usceptibility oof P. aeruginoosa is ≤64 mgg/L. Results of the
internalsu
urveyareillusstratedinTable1and2belo
ow:
aPTZMIC;201
11
Table1:CombinedICU:P.aeruginosa
Susceptible
In
ntermediate/
Resistant
MIC
≤8
16
32
2
6
64
>64
Totall
#isolates
82
11
3
7
21
124
Allhospitalisolates:P.aerug
ginosaPTZMIC;2011
Table2:A
In
ntermediate/
Susceptible
Resistant
MIC
≤8
16
6
32
3
64
>64
Totall
#isolates
348
48
8
10
1
38
65
509
h
may potentiaally be sub‐op
ptimally treatted by
These datta reveal thatt 22% (n=96) of isolates hospital‐wide
traditionaaladministratiionofPTZ.Continuingwith
hthecurrentp
practicecould
dresultinaneegativeoutcom
mefor
a number of patients per
p year cared
d for at <<HO
OSPITAL>>. Booth ICU and n
non‐ICU settin
ngs are affectted by
drugsusceptib
bility,withsev
veralpatientsaffectedonth
henon‐ICUgeeneralwards.
impairedd
c
relevaance of these findings has also been in
nvestigated. In one such study,
Clinical sttudies. The clinical
outcomes were examined in patien
nts before an
nd after imp lementation of a hospitall‐wide substitution
2 programwhereintermittentlyinfusedPTZwasautomaticallyconvertedtoEI.5Inpatientsatgreatestrisk
formortality(APACHEIIscore≥17)EIPTZresultedinsignificantlylower14‐daymortalityrates(12.2%vs.
31.6%, p=0.04) and median hospital length of stay (LOS) (21 days vs. 38 days, p=0.02) compared with
patientswhoreceivedintermittentinfusionPTZ.
Furthermore,in a recentmeta‐analysis,the authors noteda reduced mortality amongpatientsreceiving β‐
lactamagentsadministeredbyEIcomparedtothosereceivingintermittentinfusions.6
Economic evaluation. In the previous study, EI PTZ resulted in reduction of total daily dose by 25%‐50%
representingconsiderablesavingsinannualdirectdrugacquisitioncosts.5
Projected expenditures for automatic therapeutic interchange to PTZ 3.375g (infused over 4 hrs) q8h at
<<HOSPITAL>>aresummarizedinTable3.BasedonPTZutilizationdatafromfiscalyear2012,aprojected
costsavingsofapproximately$150,000mayberealizedwithaswitchtoextendedinfusionPTZ.
Table3.ProjectedFinancialImpactofPTZProlongedInfusionat<<HOSPITAL>>inFY2013
PTZDose
Cost/day/patient
FY13Total
3.375gIVq6h
$44
$602,250
3.375gIVq8h
$33
$451,688
Difference
$11
$150,562
ALTERNATEDOSINGPROPOSAL:
Patientpopulationsimpacted:Adultpatientshospitalizedat<<HOSPITAL>>onadultwards
Procedure:Ordersforstandarddoses/administrationofPTZforadultswillbeinterchangedwithextended‐
infusion as described in Table 4. Pharmacists will assist providers in adjusting the dose of PTZ for renal
functionasindicatedinthechartbelow:
Table4.AdjustmentofEIPiperacillin/tazobactamDosingBasedonRenalFunction4,7
Clcr(mL/min)
Over20mL/min
≤20mL/min(including
ContinuousRenal
peritonealorhemodialysis)
ReplacementTherapy
(CRRT)
Pip/TazoDose
3.375gIVover4hours
3.375gIVover4hours
3.375gIVover4hoursq8h
q8h
q12h
ExceptionstothePolicy
Doseadjustments:Certainpopulationswithenhanceddrugclearance,suchascriticallyillpatientswithsevere
infectionsorpatientswithcysticfibrosis,maybenefitfrommoreintensivePTZdosingtomaximize%fT>MIC.
However,doseintensificationstudiesinthesepopulationsarelimitedandrequirefurtherelucidation.Itis
notrecommendedtoincreasethedosebeyond3.375gq8hwithoutcarefulconsiderationofpatient‐specific
factorsincludingseverityofillnessandMICoftheorganism.
EmergencyDepartment(pre‐admissionstatusonly),ORandPACUareas,andambulatoryclinics:Patientswith
orders for PTZ from these areas for which 4‐hour infusion times may not be practical may receive a
traditionalstandard30‐minuteinfusionatthediscretionofthephysicianand/ornursingstaff.Subsequent
extended‐infusiondosesshouldbeadministered6‐8hoursaftertheintermittentdose.
Medicationschedulingand/ordrugcompatibilityconflicts:Clinicalpharmacistswillalsobeavailabletoassist
nursing to help resolve medication scheduling and compatibility issues (see Appendix A). If shifting
medication administration times does not alleviate the problem, nursing may request standard 30‐min
3 infusionsafterconsultingwiththepharmacistandphysician.Placingnewlinestoaccommodateextended‐
infusion PTZ is discouraged, and should only be done upon the discretion of the attending physician or
InfectiousDiseasesConsultTeaminwhichthebenefitsarebelievedtooutweighanyrisks.
IMPLEMENTATIONTIMELINE:
Extended‐InfusionPTZImplementationComponent
SuggestedTime
EIPTZProtocolASETreview
February2013
EIPTZProtocolP&Treview
March2013
Pharmacisteducation
March2013–April2013
Nursing/physicianeducation(allow4‐6weekspriortoimplementation
forpharmacist‐leadinservicepresentationsanddistributionof
educationalhandouts)
E‐browserCPOE/HMMimplementation
April15,2013
EPICimplementation
June22,2013
6monthauditandfeedbackdatacollection
Sept2013
REFERENCES:
1. Craig WA, Ebert SC. Continuous infusion of beta‐lactam antibiotics. Antimicrob Agents Chemother 1992;
36:2577‐2583.
2.GrantE,NicolauDP,NightingaleCH,QuintilianiR.Continuousinfusionofbeta‐lactamantibiotics.ConnMed
1999;63:275‐277.
3. Lodise TP, LomaestroB, RodvoldK, DanzigerL, DrusanoG. Pharmacodynamic profiling of piperacillin in
the presence of tazobactam in patients through the use of population pharmacokinetic models and Monte
Carlosimulation.AntimicrobAgentsChemother2004;48(12):4718‐24.
4. Lodise TP, LomaestroB, DrusanoG. Application of antimicrobial pharmacodynamic concepts into clinical
practice:focusonβ‐lactamantibiotics.Pharmacotherapy2006;26(9):1320‐1332.
5.LodiseTP,LomaestroB,DrusanoG.Piperacillin‐tazobactamforPseudomonasaeruginosainfection:clinical
implicationsofanextended‐infusiondosingstrategy.ClinInfectDis2007;44(3):357‐63.
6. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with continuous or extended versus
short‐term intravenous infusion carbapenems and piperacillin/tazobactam: a systematic review and meta‐
analysis.ClinInfectDis2013;56(2):272‐82.
7. Patel N, Scheetz MH, Drusano GL, Lodise TP. Identification of optimal renal dosage adjustments for
traditional and extended‐infusion piperacillin/tazobactam dosing regimens in hospitalized patients.
AntimicrobAgentsChemother2010;54(1):460‐65.
8. Trissel LA. Piperacillin sodium‐tazobactam sodium. Handbook on Injectable Drugs 16th ed. 2011:1279‐
1287.
January2013
Preparedby:ChristinaSarubbi,Pharm.D.
Reviewedby:DeverickAnderson,MD,MPH;RichardDrew,PharmD,MS;RebekahMoehring,MD,MPH;
MichelleSharpe,PharmD
4 AppendixA.CompatibilityofSelectDrugswithPTZadministeredbyintermittentorcontinuous
infusion8
The standard concentration of PTZ 3.375g mini‐bag with a total volume of 100 mL = 33 mg/mL. More
comprehensivelistingsofcompatibleandincompatibledrugsmaybefoundindrug‐dosinghandbooks.
Y‐sitecompatible[CanbeY‐sitedtogetherwiththeseintermittentorcontinuousIVmeds]
Antibiotics
Other
GI/Reflux
Anticoagulants
Amikacin
Bivalirudin
Pantoprazole
Allopurinol
Aztreonam
Heparin
Metoclopramide
Digoxin
Cefepime
Ranitidine
Diphenhydramine
Clindamycin
Magnesiumsulfate
Diuretics
Metronidazole
Mannitol
Bumetanide
Pressors
TMP/SMX(Bactrim®)
Methylprednisolone
Dopamine
Furosemide
PotassiumChloride
Tigecycline
Norepinephrine
Potassiumphosphate
Phenylepherine
Drips
Antifungals
Vasopressin
Fentanyl
AmphotericinB
Lorazepam
liposomal(Ambisome®) Morphine
AmphotericinBlipid
SodiumBicarbonate
complex(Abelcet®)
Fluconazole
Voriconazole
NOT‐COMPATIBLE‐[DoNotPiggybackTogether]
Antibiotics
Other
Other
Antivirals
Azithromycin
Acyclovir
Chlorpromazine
Haloperidol
Ciprofloxacin
Diltiazem
Insulin,regular
Doxycycline
Antifungals
Dobutamine
Promethazine
Micafungin
Gentamicin
Famotidine
Nalbuphine
Levofloxacin
Midazolam
Moxifloxacin
Propofol
Tobramycin
Vancomycin**
**VariablecompatibilityviaY‐site:
Variable compatibility has been reported for vancomycin and PTZ and is concentration‐dependent.
Vancomycinconcentrationsatorexceeding20mg/mLareincompatiblewithallconcentrationsofPTZ.PTZ
concentrations of 45 mg/mL are compatible with vancomycin concentrations of <=2 mg/mL but this
concentration of vancomycin is not typically used. Thus, vancomycin and PTZ should be considered
incompatible.
5