1
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
2
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
3
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)
4
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
5
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
6
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
7
PK/PD parameters affecting antibiotic PK/PD parameters affecting antibiotic efficacy efficacy in vivoin vivo
0
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)
0
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
8
Shorten T>MIC in resistance pathogenShorten T>MIC in resistance pathogen
Cmax = maximum plasma concentration
CCmaxmax:MIC:MIC (aminoglycosides)(aminoglycosides)
0
Cmax:MIC
Concentration
Time (hours)
MIC
Target value: Cmax:>8–10 MIC
9
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
10
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
11
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
13
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
15
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
16
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
17
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
18
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