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Name : Lie Khie Chen Birth : Jakarta Graduates

MD : FKUI 1994Internist : FKUI 2003Consultant : FKUI 2006

Occupation Internal Medicine DepartmentTropical Medicine and Infectious Diseases Division 2003

Interest SepsisNosocomial infectionFungal InfectionExtrapulmonary TBHIV and opportunistic infections

Curriculum Vitae

Application of PKPD in Application of PKPD in Clinical Practice Clinical Practice

Khie ChenKhie Chen

Division of Tropical Medicine and Infectious Diseases Division of Tropical Medicine and Infectious Diseases Department of Internal MedicineDepartment of Internal Medicine

Faculty of Medicine University of IndonesiaFaculty of Medicine University of IndonesiaDr. Cipto Mangunkusumo HospitalDr. Cipto Mangunkusumo Hospital

JAKARTAJAKARTA

Antimicrobial Treatment based on Antimicrobial Treatment based on Microbiological Culture ResultsMicrobiological Culture Results

Microbiological culture resultsMicrobiological culture results

Colonization PathogenColonization Pathogen

No treat Sensitive ResistantNo treat Sensitive Resistant

Treat with Antibiotics OptimizedTreat with Antibiotics OptimizedRecommended Combination PKPDRecommended Combination PKPDAntibioticsAntibiotics

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Outcome in Antimicrobial UsageOutcome in Antimicrobial Usage

nn Clinical outcomeClinical outcomenn Microbiological outcomeMicrobiological outcome

Consideration When Using Antimicrobial Agents

Microbiology§ Mechanism of action§Antibacterial spectrum

DrugPK

§ Absorption§Distribution§Metabolism§ Excretion§Optimal dosing

regimen

Concentrationat infection site

Pathogen MIC

PD§ Time vs. concentration

dependent killing§ Bactericidal vs. bacteriostatic

activity§ Tissue penetration§ Persistence of antibacterial effect

Outcome§ Clinical efficacy§ Bacterial eradication§ Compliance with

dosing regimen§ Tolerability§ Rate of resolution§ Prevention of resistance

(Scaglione, 2002)

Parameters of Antimicrobial Activity

• Potency : MICMBC

• Time Course of ActivityRate of killingPersistent effects

PAE, PA-SME,PALE

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Timed Kill CurvesRate of bacterial killing in certain antimicrobial (or combination) and microorganism

MICMIC

nn Minimum inhibitory concentrationMinimum inhibitory concentrationnn in mg/L or ug/mLin mg/L or ug/mLnn Is the lowest concentration in a series of twofold Is the lowest concentration in a series of twofold

concentrations that will inhibit the growth of a concentrations that will inhibit the growth of a microorganism, as measured by the naked eye.microorganism, as measured by the naked eye.

nn Convention : series concentration shall contain Convention : series concentration shall contain the 1 mg/L concentrationthe 1 mg/L concentrationie 0.25 ie 0.25 -- 0.5 0.5 -- 1 1 –– 2 2 –– 4 4 -- 8 8 –– 32 32 --64 64 -- 128128

MIC breakpointMIC breakpoint

nn Value of MIC that correlate with the outcomeValue of MIC that correlate with the outcomenn MIC break point:MIC break point:

-- Clinical breakpointClinical breakpoint-- Non species related breakpoint :Non species related breakpoint :PKPD breakpoint, Monte Carlo simulationPKPD breakpoint, Monte Carlo simulation

-- Epidemiological cut off (ECOFF)Epidemiological cut off (ECOFF)

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Microbiological Lab reportMicrobiological Lab report

nn Susceptible/sensitive:Susceptible/sensitive:in level of antimicrobial activity associated with in level of antimicrobial activity associated with a high likelihood of therapeutic successa high likelihood of therapeutic success

nn IntermediateIntermediateuncertain therapeutic effectuncertain therapeutic effect

nn ResistantResistantassociated with therapeutic failureassociated with therapeutic failure

SusceptibilitySusceptibility

nn MIC methodMIC methodlowest MIC is more sensitivelowest MIC is more sensitive

nn Zone diameterZone diameterwider diameter is more sensitivewider diameter is more sensitive

ResistanceResistance

nn Above cut off MICAbove cut off MICnn Below cut off diameter zoneBelow cut off diameter zonenn Probability of failureProbability of failure

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MIC and Drug efficacyMIC and Drug efficacy

MIC is related to potency of the drugMIC is related to potency of the drug( in vitro )( in vitro )

PK is related to exposure to the bugPK is related to exposure to the bug( in vivo )( in vivo )

MIC PK relationshipMIC PK relationship

nn Relationship between MIC in vitro and Relationship between MIC in vitro and concentration in vivoconcentration in vivo

nn Related to :Related to :dosing regimendosing regimendrug applicationdrug application

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Pharamacokinetic : Concentration-Time

PK parameters:Cmax : peakC min : troughVdT½ : half lifeAUCClearenceProtein binding

Pharmacodynamic : ability to killPharmacodynamic : ability to kill

Time dependentT>MIC

Concentration dependentCmax , AUC>MIC

PKPD relationshipPKPD relationship

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PK/PD parameters affecting antibiotic PK/PD parameters affecting antibiotic efficacy efficacy in vivoin vivo

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MIC

AUC:MIC

T>MIC

Cmax:MICConcentration

Time (hours)

PAE

MIC = minimum inhibitory concentration; AUC = area under the curve; T = time; PAE = post antibiotic effect

Time dependentT>MIC (CEF)

Concentration dependentCmax>MIC (AM)AUC/MIC (FQ)

Antibiotic Characteristic base on PKPDAntibiotic Characteristic base on PKPD

Con

cent

ratio

n

Time (hours)

Cmax = Peak

Cmin = Trough

MIC

T > MIC

Cmax / MICAminoglycosides1,2

Fluoroquinolones1,2

Penicillins1

Cephalosporins1

Carbapenems1

Macrolides1,2

Glycopeptides2

Lincosamides2

AUC / MICAminoglycosides2

Fluoroquinolones1,2

Oxazolidanones1,2

Glycopeptides2

Lincosamides2

Lipopeptides1,2

Tetracyclines2

Macrolides2

1. Nicolau DP. J Infect Chemother. 2003;9:292-296.2. Ambrose PG, et al. Clin Infect Dis. 2007;44:79-86.

Concentration Dependent

T>MICT>MIC ((ββ--lactams)lactams)

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T>MIC

Concentration

Time (hours)

MIC

Target value: 1. T>MIC in 40%–60% of dosing interval2. Css>4–5 MIC

Turnridge. Clin Infect Dis 1998;27:1022; Manduru, et al. Antimicrob Agents Chemother 1997;41:2053–2056; Tam, et al. J Antimicrob Chemother 2002;50:425–428; Tam, et al. Antimicrob Agents Chemother 2005;49:4920

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Shorten T>MIC in resistance pathogenShorten T>MIC in resistance pathogen

Cmax = maximum plasma concentration

CCmaxmax:MIC:MIC (aminoglycosides)(aminoglycosides)

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Cmax:MIC

Concentration

Time (hours)

MIC

Target value: Cmax:>8–10 MIC

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0

AUC:MIC

Concentration

Time (hours)

MIC

AUC:MICAUC:MIC (fluoroquinolones)(fluoroquinolones)

Target value: 1. Gram-positiveAUC/MIC >302. Gram-negativeAUC/MIC >125

Ambrose, et al. Antimicrob Agents Chemother 2001;45:2793–2797;Forrest, et al. Antimicrob Agents Chemother 1993;37:1073–1081

Relationship between Cmax/MIC and clinical Relationship between Cmax/MIC and clinical response in Aminoglycoside treatmentresponse in Aminoglycoside treatment

Moore et al. J Infec Dis 1987;155:93

PKPD of AminoglycosidePKPD of Aminoglycoside

nn AUC/MIC and Peak/MIC is important indices AUC/MIC and Peak/MIC is important indices in determining efficacyin determining efficacy

nn 24 hr AUC/MIC >100 along peak/MIC 824 hr AUC/MIC >100 along peak/MIC 8--10 10 require for 90% of efficacyrequire for 90% of efficacy

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Efficacy of Tobramycin Monotherapy in Efficacy of Tobramycin Monotherapy in Gram negative Bacilli infectionsGram negative Bacilli infections

nn 23 patients with nosocomial pneumonia or IAI23 patients with nosocomial pneumonia or IAI

24 hr AUC/MIC > 110 : 80 % clinical cure24 hr AUC/MIC > 110 : 80 % clinical cure24 h AUC/MIC < 110 : 47 % p<0.0124 h AUC/MIC < 110 : 47 % p<0.01

Smith et al. Clin Ther 2001; 23:1231Smith et al. Clin Ther 2001; 23:1231

Pharmacokinetic of betalactamPharmacokinetic of betalactam

nn For betaFor beta--lactams in general, the time drug concentration lactams in general, the time drug concentration exceeds the MIC (T>MIC) is predictive of antibacterial activityexceeds the MIC (T>MIC) is predictive of antibacterial activity

nn Carbapenems have the shortest % T>MIC requirement Carbapenems have the shortest % T>MIC requirement compared to penicillins and cephalosporinscompared to penicillins and cephalosporins

% T> MIC*% T> MIC*Bacteriostatic Bacteriostatic

(%)(%)BactericidalBactericidal††

(%)(%)CephalosporinsCephalosporins 3535--4040 6060--7070PenicillinsPenicillins 3030 5050CarbapenemsCarbapenems 2020 4040

* Percentages relate to free drug concentration time greater than MIC† 3-log reduction in colony forming units.

Drusano GL. NATURE REVIEWS / MICROBIOLOGY 2004 (April);2:289-300; Craig WA Clin. Infec. Dis. 1998; 26, 1-12; Zhanel G et al. Drugs. 2007;67:1027-1052.

PDPD target target attainment (%) against attainment (%) against P.P. aeruginosaaeruginosa in children in in children in twotwo hospitalshospitals

HospitalHospital

11 22MeropenemMeropenem 20 mg/kg q820 mg/kg q8hh 8484 4747

40 mg/kg q840 mg/kg q8hh 9494 5858

ImipenemImipenem 15 mg/kg q615 mg/kg q6hh 8787 5454

25 mg/kg q625 mg/kg q6hh 9292 5757

CCeftazidimeeftazidime 50 kg/kg q850 kg/kg q8hh 9292 6565

CCefepimeefepime 50 mg/kg q850 mg/kg q8hh 8585 7878

PPip/tazoip/tazo 75 mg/kg q675 mg/kg q6hh 6060 4747

Ellis, et al. Clin Ther 2005;11:1820–1830

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Improving the PD attainment rate by Improving the PD attainment rate by prolonging the prolonging the ββ--lactam infusion timelactam infusion time

30 min30 min 3 hr3 hr 4 hr4 hrIncrease*Increase*

(%)(%)

MeropenemMeropenem 1 g q8h1 g q8h 77.177.1 83.883.8 —— +6.7+6.7

2 g q8h2 g q8h 84.184.1 88.188.1 —— +4.7+4.7

Pip/tazoPip/tazo 4.5 g q8h4.5 g q8h 56.456.4 —— 80.780.7 +24.3+24.3

Ludwig, et al. Int J Antimicrob Agents 2006;28:433–438

*PD attainment

Effect of Doripenem Extended Effect of Doripenem Extended Infusion on %T > MICInfusion on %T > MIC

Dose 500 mg 1 h 500 mg 4 h 1500 mg 24 h

Dor

ipen

em C

once

ntra

tion

(mg/

L)

Time Since Start of Infusion (h)

MIC = 4

32

16

8

4

2

10 642 8 10 12

31% 49%T>MIC

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Target attaintment when using Target attaintment when using difference regimen of doripenemdifference regimen of doripenem

Clinical Efficacy of Doripenem for Clinical Efficacy of Doripenem for Lower Respiratory Tract InfectionsLower Respiratory Tract Infections

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Criteria for susceptibility of S aureus to vancomycin

l Susceptible ≤4µg/mL

l Intermediate = 8 to 16µg/mL (VISA)

l Resistant ≥32µg/mL (VRSA)

VISA = vancomycin-intermediate S aureus. VRSA = vancomycin-resistant S aureus.National Committee for Clinical Laboratory Standards (NCCLS). 2002;22:96-100.

In vitro susceptibility

Antibiotic-resistant gram-positive cocci

OrganismOrganismMIC90 (mg/L) of each antibioticMIC90 (mg/L) of each antibiotic

VancVanco*o* TeicoplaninTeicoplanin**

Linezolide*Linezolide*** Tigecyclin*Tigecyclin*

VISA VISA 88 88 NDND 0.50.5MRSAMRSA 11 11 1.61.6 0.50.5MSSAMSSA 11 0.50.5 1.61.6 0.50.5MRMR--CNSCNS 22 1616 2.92.9 11VREVREfecfec > 32> 32 > 32> 32 <1.7<1.7 0.50.5VREfcm VREfcm > 32> 32 > 32> 32 1.71.7 0.120.12PRSPPRSP 0.250.25 0.0080.008 11--22 0.250.25

Petersen PJ, et al. Antimicrob Agents Chemother. 2002;46:2595.Data on file Pharmacia and Upjohn Company

Although a useful guide, in vitro activity does not necessarily correlate with clinical response.

PK of GlycopeptidePK of Glycopeptide

nn PK efficacy parameter : 24hr AUC/MIC > 400PK efficacy parameter : 24hr AUC/MIC > 400nn Conventional dosing strategy fail when MIC Conventional dosing strategy fail when MIC >> 22nn C trough need to be > 20 ug/mLC trough need to be > 20 ug/mLnn Continuous infusion maintaining 20 ug/mL may Continuous infusion maintaining 20 ug/mL may

fail to yeald 24hr AUC/MIC > 400fail to yeald 24hr AUC/MIC > 400nn When MIC When MIC >> 2 intermittent dosing is 2 intermittent dosing is

recommendedrecommended

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0

Concentration

Time (hours)

MIC

24 hour Area Under Curve24 hour Area Under Curve24 H AUC : cummulative dosage in 24 HRelated to efficacy and drug toxicityTarget Attaintment : 24 H AUC/MIC : 125

if MIC = 2 24 H AUC : 250average concentration 250/24 : 10 ug/mL

Ambrose, et al. Antimicrob Agents Chemother 2001;45:2793–2797;Forrest, et al. Antimicrob Agents Chemother 1993;37:1073–1081

Time

Vancomycin troughVancomycin troughplasma concentrations: PPplasma concentrations: PP

Treatment day nMean

concentration (µg/mL)

Median concentration

(µg/mL)

Concentration range

(µg/mL)

3 140 14.1 12.3 2.8-50.8

6 90 16.9 14.7 2.7-45.0

9 33 17.4 16.1 2.0-46.9

• As a double-blind study, only the research pharmacist and unblinded monitor were aware of the levels

Kunkel, Chastre et al. Oral presentation LB-49 at 48th IDSA,21-24 October 2010, Vancouver, Canada

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Clinical response by maximum vancomycin Clinical response by maximum vancomycin trough concentrations at either day 3, 6 or 9 trough concentrations at either day 3, 6 or 9

(mITT at EOS)(mITT at EOS)

0-11.35 (µg/mL)n=41n (%)

>11.35-15 (µg/mL)n=42n (%)

>15-22.2 (µg/mL)

n=36n (%)

>22.2 (µg/mL)

n=38n (%)

Success 20 (48.8) 20 (47.6) 17 (47.2) 17 (44.7)

Failure 21 (51.2) 22 (52.4) 19 (52.8) 21 (55.3)

• As a double-blind study, only the research pharmacist and unblinded monitor were aware of the assignment

Kunkel, Chastre et al. Oral presentation LB-49 at 48th IDSA,21-24 October 2010, Vancouver, Canada

Clinical success rates Linezolid vs Clinical success rates Linezolid vs Vancomycin in MRSA Pneumonia Vancomycin in MRSA Pneumonia

PP at EOS mITT at EOS PP at EOT mITT at EOT0

20

40

60

80

100Clinical success rate (%)

57.6%95/165

54.8%102/186

83.3%150/180 80.1%

161/201

46.6%81/174

44.9%92/205

69.9%130/186

67.8%145/214

LinezolidVancomycin

p=0.042 p=0.04

9

p=0.002

p=0.004

Kunkel, Chastre et al. Oral presentation LB-49 at 48th IDSA,21-24 October 2010, Vancouver, Canada

Application of PKPDApplication of PKPDnn MDROMDROnn Critically Ill PatientsCritically Ill Patientsnn Immune compromisedImmune compromisednn NeutropenicNeutropenic patientspatients

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Application of PKPDApplication of PKPD

Time DependentTime Dependentnn Intermitten dosingIntermitten dosingnn Prolong infusionProlong infusionnn Continuous infusionContinuous infusion

Concentration Concentration DependentDependentnn Once daily dosingOnce daily dosing

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