pharmacokinetics in critical patient

8/16/2019 Pharmacokinetics in critical patient

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Antimicrobial Pharmacokinetics/dynamicsAntimicrobial Pharmacokinetics/dynamicsBedside Applications in the Critically IllBedside Applications in the Critically Ill

Arthur RH van Zanten, MD PhDInternist-intensivistDepartment of Intensive careGelderse Vallei Hospital, EdeThe Netherlands


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TreatmentTreatment of ICUof ICU patientspatients withwith antibioticsantibioticsfromfrom aa clinicalclinical perspectiveperspective

Bacterial infection

Best antibiotic

Optimum effect

Bacterial eradication&

clinical efficacy

Avoid toxicity&

adverse effects


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InappropriateInappropriate therapytherapy and VAPand VAP mortalitymortality

Alvarez-Lerma F. Intensive Care Med. 1996 May;22(5):387-94Celis R Chest. 1988 Feb;93(2):318-24Kollef MH Chest. 1998 Feb;113(2):412-20Luna CM Chest. 1997 Mar;111(3):676-85.Rello J Am J Respir Crit Care Med. 1997 Jul;156(1):196-200


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Timing of adequateTiming of adequate antibioticsantibiotics in septicin septicshockshock

KumarKumar .. CritCrit Care Med 2006;34:1589Care Med 2006;34:1589 --15961596

Time in hours afterdocumented hypotension

%

N = 2154


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AntibioticAntibiotic dosingdosing strategiesstrategies inin renalrenal failurefailure ininICUICU

Underdosing Toxicity

Reducedelimination

Severeinfections

Immunocompromisedhost

Nosocomial pathogens

Resistance

Clinical data

CRRT

?


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AntibioticsAntibiotics , PK in, PK in wardswards and ICUand ICUHydrophilicantibioticsHydrophilicHydrophilicantibioticsantibiotics

Low VdPredominant renal Cl

Low intracellular penetration

Increased VdCl higher or lower

dependent on renal function

Beta-lactamsAminoglycosides

GlycopeptidenLinezolidColisitin

Lipophilic antibioticsLipophilicLipophilic antibioticsantibiotics

High VdPredominant hepatic Cl

Good intracellularpenetration

Vd largely unchangedCl higher or lower

dependent on hepaticfunction

FluoroquinolonesMacrolides

LincoamidesTigecycline

General PK

Altered ICU PK

Examples

Roberts.Roberts. CritCrit Care Med;37:840Care Med;37:840 --851851


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SepsisSepsis

EndEnd OrganOrganDysfunctionDysfunction (e.g.(e.g.renalrenal oror hepatichepatic ))

NormalNormal organorganfunctionfunction

LeakyLeaky CapillariesCapillaries&/ &/ oror alteredaltered

proteinprotein bindingbinding

IncreasedIncreased CardiacCardiacOutputOutput

DecreasedDecreased ClClUnchangedUnchanged VdVdIncreasedIncreased VdVdIncreasedIncreased ClCl

High plasmaHigh plasmaconcentrationsconcentrations

NormalNormal plasmaplasmaconcentrationsconcentrations

LowLow plasmaplasmaconcentrationsconcentrations



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AntibioticsAntibiotics changeschanges inin HalfHalf --lifelife

Increased renal perfusionDecreased renal perfusionRenal failureCapillary leakage

Gold-standard: creatinineclearance (2-hours CL?)

Hypalbuminemia(e.g. cetriaxone 95%albumin bound in normalsubjects)

T1/2 = 0.693 x VdCl



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Continuous Renal Replacement TherapyContinuous Renal Replacement Therapy

AAanvoeranvoer

TeruggaveTeruggave

EffluentEffluent

SCUF CVVH CVVHD CVVHDF

SubstitutieSubstitutie(pre o(pre o ff postpostdilutidiluti ee ))

AanvoerAanvoer

teruggaveteruggave

EffluentEffluent

AAanvoeranvoer

TeruggaveTeruggave

EffluentEffluent

DialysaatDialysaat

SubstitutieSubstitutie(pre o(pre o ffpostpost dilutidiluti ee ))

I

AanvoerAanvoer

TeruggaveTeruggave

EffluentEffluent

DialysaDialysa atat


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Convective Elimination during CVVHConvective Elimination during CVVH

membrane

Blood flow in

Ultrafiltrate

H em

of i l t er

Blood

Blood flow out

Sieving Coefficient (SC)Sieving Coefficient (SC)

SC =SC =

[UF][UF]

[Blood][Blood]

ClClCVVHCVVH = SC X= SC X

QQ UFUF


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BasicBasic principlesprinciples

Extracorporeal clearance (Cl EC ) is usually considered clinicallysignificant only if its contribution to total body clearanceexceeds 25 - 30%

FrEC = Cl ECClEC + Cl R + Cl NR

Not relevant for drugs with high non-renal clearance

Only drug not bound to plasma proteins can be removed by

extracorporeal procedures (unbound protein of a drug Fup)SchetzSchetz .. CurrCurr OpinOpin critcrit Care 2007;13:645Care 2007;13:645 --5151


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LoadingLoading dosedoseMainly depends on Vd, not eliminationReflection of volume to dissolve drugNo adjustment in renal failure or CVVH

Vd affected by:◦

Total body water◦ Tissue perfusion◦ Protein binding◦ Lipid solubility◦ pH gradients◦ Active transport mechanismsIncreased loading dose may be required in critically ill

BoumanBouman .. CurrCurr OpinOpin CritCrit Care;14:654Care;14:654 --659659


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P o o r a c t i v i t y P o o r a c t i v i t y

EfficacyEfficacy and Pharmacodynamicsand Pharmacodynamics

Time after taking drug

D r

u gl ev el i n

b l o

o d

Peak Peak

Cmin

Cmax

Trough

IC50

U n a c c e p t a b l e t o x i c i t y

IC90


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Pharmacodynamic Indices predictive forPharmacodynamic Indices predictive forefficacyefficacy

T > MIC Cmax / MIC AUC 0-24 / MIC

Time-dependent Concentration-dependent Concentration-dependent with time-

dependencePenicillins Aminoglycosides Aminoglycosides

Cephalosporins Fluoroquinolones Fluoroquinolones

Carbapenems Metronidazole Metronidazole

Monobactams Daptomycin Quinupristin

Macrolides Azithromycin

Lincoamides Glycopeptides

Linezolid Tetracyclines


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Ciprofloxacin serum concentrationsCiprofloxacin serum concentrationsafter single bolus IVafter single bolus IV

0

10

20

30

4050

60

70

80

90100

[ c i p r o

f l o x a c

i n ]

t in hours

Ciprofloxacin pharmacokinetics in critically

ill patients: A prospective cohort study.J Crit Care 2008 Arthur R.H. van Zanten, et al


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Quinolones: AUC/MIC > 125Quinolones: AUC/MIC > 125

AUC above MICAUC above MIC

Cmax/MIC (>10)Cmax/MIC (>10)

AUC24/MICAUC24/MIC

Ciprofloxacin: 100Ciprofloxacin: 100 --125125

Schentag. J Chemother 1999 Dec;11(6):426Schentag. J Chemother 1999 Dec;11(6):426 --3939


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Volume of distribution (Vd) of ciprofloxacinVolume of distribution (Vd) of ciprofloxacin400 mg bid IV in 32 critically ill patients400 mg bid IV in 32 critically ill patients

A.R.H. van Zanten. J Crit Care 2008A.R.H. van Zanten. J Crit Care 2008


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AUC 1AUC 1 --24 ciprofloxacin 2 x 400 mg IV in 3224 ciprofloxacin 2 x 400 mg IV in 32

critically illcritically illAUC/MIC > 100 for different MIC levelsAUC/MIC > 100 for different MIC levels

020

406080

100120140160180200

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

AUC

patientCiprofloxacin pharmacokinetics in critically

ill patients: A prospective cohort study.J Crit Care 2008 Arthur R.H. van Zanten, et al


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Pseudomonas aeruginosa isolatesPseudomonas aeruginosa isolates

Eucast wild type MIC distribution for ciprofloxacin

Risk subtherapeutic dosing with 400 mg bid


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ββ --lactam Pk/Pdlactam Pk/Pd

MIC90

Time above MIC

Time

Time above MIC

• How long?• For all bacteria?• For all β -lactams?• Influence pharmacokinetics?


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ββ --lactam static effects: streptococcilactam static effects: streptococci

0 10 20 30 40 50 60 70 80 90

3

2

1

0

-1

-2

-3

-4

-5

-6

R2 = 89%

T > MIC (%)

Antimicrob Agents Chemother 2008;52:3492Antimicrob Agents Chemother 2008;52:3492 --66


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ββ --lactam specific pharmacodynamics: T>MIClactam specific pharmacodynamics: T>MIC

0 10 20 30 40 50 60 70 80 90

3

2

1

0

-1

-2

-3

-4

-5

-6 T > MIC (%)

Andes, Craig. Int J Antimicrob Agents 2002;19:261Andes, Craig. Int J Antimicrob Agents 2002;19:261 --88


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More antibiotic specific: T > MIC for staticMore antibiotic specific: T > MIC for staticeffecteffect

T>MIC static effect Enterobacteriacieae% T > MICS. Pneumoniae

% T > MIC

Ceftriaxon 38 (34-42) 39 (37-41)

Cefotaxime 38 (36-40) 38 (36-40)

Ceftazidime 36 (27-42) 39 (35-42)

Meropenem 22 (18-28) -

Imipenem 24 (17-28) -

Andes, Craig. Int J Antimicrob Agents 2002;19:261Andes, Craig. Int J Antimicrob Agents 2002;19:261 --88


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Ways to prolong duration ofWays to prolong duration of ββ --lactamlactamconcentrations over MICconcentrations over MIC

1. Use another drug (eg, probenecid) that interferes with itselimination.

2. Dose frequently.3. Increase the dose of the antibiotic.4. Replace it with another therapeutically equivalent antibiotic

with a longer serum half-life (T 1/2 ).5. Administer it by constant infusion.

Quintiliani Infect Med 21(5):219Quintiliani Infect Med 21(5):219 --233, 2004233, 2004


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Randomised, prospective, open single centre study in 93 COPDpatients

suspected or proven pulmonary infection: cefotaximecontinuous infusion: 1 gr loading dose iv, 2 gr/24 hr vs.intermittent infusion: 3 x 1 gr = equivalent

More optimal drug levels at the end of dosing interval during

continuous infusion


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Pharmacokinetics of cefotaxime in 44 ICU patientsPharmacokinetics of cefotaxime in 44 ICU patients

P MIC although 1 gram lower dailydosedose


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Systematic review on clinical benefits of continuousSystematic review on clinical benefits of continuousadministration of betaadministration of beta --lactan antibioticslactan antibiotics

Systematic review 14 RCTs (from 59 studies)No difference in clinical cure rateNo difference in mortalityAll studies except one used higher dosages in the bolusgroup potentially favouring this treatment arm

The limited data available suggest that CI leads to the sameclinical results as higher dosed bolus administration inhospitalized patients

Roberts, Lipmans et al Crit Care Med 2009; 37:2071-2078


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The jury is still out on continuous infusion of betaThe jury is still out on continuous infusion of beta --lactam antibiotics in critically ill patientslactam antibiotics in critically ill patients

Advantages

Lower drug acquisitioncostsReduction of work loadTDM more easy

Disadvantages

Adequate drug levels later(loading dose)Stability of the antibiotic

High MIC, all drug levelssubtherapeutic

Van Zanten ARH. Crit Care Med 2009; 37:2137-2138

A well-designed large prospective study on potential advantages of continuousadministation of beta-lacta antibitics in ICU patients is warranted


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Total costs of intravenous antibiotic administrationTotal costs of intravenous antibiotic administrationusing different methods of administrationusing different methods of administration

Procedure Timerequired

(SD) (min:s)

Hourlywages

( € )

Time costs( € )

Materialscosts ( € )

Total costs( € )

Volumetricpump

5:04 (2:29) 21.90 01.85 02.06 03.91

Syringe pump 4:56 (2:03) 21.58 01.78 01.45 03.23

Bolus injection 9:21 (2:16) 74.09 11.59 00.10 11.69

Piggybackinfusion

5:51 (3:33) 19.75 01.93 03.47 05.40

Insertion of IV

catheter

10:15 (6:31) 23.51 04.02 04.30 08.32

Removal of IVcatheter

02:22 (0:36) 19.41 00.74 01.00 01.74

Importance of nondrug costs of intravenous antibiotic

therapy.Arthur RH van Zanten, et al Critical Care 2003, 7:R184-R190 (DOI 10.1186/cc2388)


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Daily costs of six antibiotics intravenously administeredDaily costs of six antibiotics intravenously administeredby syringe pumpby syringe pump

Antibiotic Dose(mg)

Dosages(n)

Drugcosts

( €) (A)

Averagetime

(min:s)

Staffcosts ( €)

(B)

Materialcosts ( €)

(C)

Administration

costs ( €)

(B+C)

Totaldaily

costs ( €)

(A+B+C)Amoxicillin/

clavulanic acid1000

/ 200

3 07.35 12:21 03.99 04.35 08.34 15.69

Cefotaxime 1000 4 49.40 18:48 06.08 05.80 11.88 61.28

Erythromycin 1000 4 54.44 36:44 11.88 05.80 17.68 72.12

Gentamicin 320 1 20.34 03:39 01.18 01.45 02.63 22.97*

Pip/Tazo 2250 3 43.14 16:31 05.40 04.35 09.75 52.89

Data presented are the medication costs, the time expenditure required, the staff wage and the disposablematerial costs for each of the antibiotics per day administrated via syringe pump. The figures quoted refer tothe total time for preparation and administration of each medication per day, averaged over wards and

indications studied. Costs are based on list prices provided by Dutch health care authorities. *If therapeuticdrug monitoring costs for gentamicin based on 24-hourly intervals would be included, the total costs would be €58.97 per day.


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The jury is still out on continuous infusion of betaThe jury is still out on continuous infusion of beta --lactam antibiotics in critically ill patientslactam antibiotics in critically ill patients

Advantages

Lower drug acquisitioncostsReduction of work loadTDM more easy

Disadvantages

Adequate drug levels later(loading dose)Stability of the antibiotic

High MIC, all drug levelssubtherapeutic

Van Zanten ARH. Crit Care Med 2009; 37:2137-2138

A well-designed large prospective study on potential advantages of continuousadministation of beta-lacta antibitics in ICU patients is warranted


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How to dose in renal failure and CVVH?How to dose in renal failure and CVVH?

Creatinine clearanceRisk of overdosing in drugs with tubular excretion andunderdosing for drugs with tubular reabsorption (e.g.fuconazole)Estimations of poor quality

Normal Dose (anuric) => Dose CVVH (ratio of normalclearance and Cl CVVH )

Anuric Dose => adjustment using maintenance dosemultiplication factor

Bouman. Curr Opin Crit Care;14:654Bouman. Curr Opin Crit Care;14:654 --659659

Dose CVVH = Dose normal X Clnonrenal +ClCVVH

Clnormal

MDMF = 11 -

FrCVVH


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Pk during CVVH various antibioticsPk during CVVH various antibiotics35 ml/kg*h 70 kg patient35 ml/kg*h 70 kg patient

Bouman. Curr Opin Crit Care;14:654Bouman. Curr Opin Crit Care;14:654 --659659


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Antimicrobial Pk/Pd: Bedside Applications inAntimicrobial Pk/Pd: Bedside Applications inthe Critically Ill with Renal Failurethe Critically Ill with Renal Failure

Pharmacokinetics in critically ill patients are highly variableLoading as normal, consider higher dose in high VdContinuous infusion is a cost-effective, work-load reducingadministration strategyContinuous infusion of beta-lactam antibiotics is feasible for severalantibiotics such as:

◦ Cefotaxime◦ Ceftazidime◦ Amoxicillin◦ Penicillin◦ Piperacillin/tazobactamDuring continuous infusion of beta-lactam antibiotics lower totaldaily dosages may be adequate due to more optimalpharmacodynamics


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Risk of underdosingRisk of underdosingHydrophylic antibioticLow protein binding (Fup high)

Large Vd, capillary leakageHigh MIC pathogen (nosocomial infections)High dose CVVHAntibiotic with high tubular reabsorption

How to increase dose?Increase dose in dose dependent killing antibiotics

More frequent dosing or continuous in time dependent antibiotics


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Antimicrobial Pk/Pd: Bedside Applications inAntimicrobial Pk/Pd: Bedside Applications inthe Critically Ill with Renal Failurethe Critically Ill with Renal Failure

In many infections in ICU patients higher ciprofloxacin dosagesshould be used even in renal failure or alternative antibiotics shouldbe consideredTherapeutic drug monitoring may be used to optimize antibiotictherapyTDM during continuous infusion does require fewer serum samplesDuring therapeutic hypothermia cefotaxime levels are 2 times highercompared to normothermiaICU Pk/Pd data are scarce

During CVVH: calculate maintenance dose multiplication factor or

TDMClinical failure could be due to underdosingTDM maybe also for non-toxic antibioticsKnow or measure MICs for common pathogens in hospital ICU

For nontoxic antibiotics overdosing is preferable to underdosing


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Thank you!Thank you!

Arthur van Zanten

[email protected]

pharmacokinetics in critical patient

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