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Meet the Expert

Application of PKPD

in Clinical Pracice

Kasus

Pria usia 67 tahun diabetes mellitus sejak 6 tahun keluhan utama luka di telapak kaki kiri yang memberat 1 minggu SMRS.

Tanda-tanda vital TD 110/70 mmHg, nadi 120 kali/menit, pernapasan 28 kali/menit cepat dan dalam dan suhu 38,4°C.

Gangren kehitaman ibu jari kiri, ulkus berdinding tegas, dasar tulang dan otot, kotor, pus (+), darah (+), jaringan nekrotik (+) berukuran 6 x 8 cm pada bagian medial telapak kaki kiri.

Kasus

Thorax PA ditemukan infiltrat para kardial

Rontgen pedis sinistra AP dan lateral tanda-

tanda destruksi tulang metatarsal dan falangs

digiti I, gas gangrene (-).

EKG dalam batas normal

USG abdomen diffuse parenchymatous liver

disease dan diffuse renal disease bilateral.

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Laboratorium

Hemoglobin 10,8

Hematokrit 33%

Leukosit 33600

Trombosit 120.000

Ureum /Kreatinin 111/4,2

AST/ALT 25/40

Bilirubin 1,1

Elektrolit (Na/K/Cl) 138/4,7/98

AGD (pH/pO2/pCO2/HCO3/O2sat) 7,36/80,3/

21,4/17,9/95,6%

PT/K 18/12

APTT/K 68/34

CRP 24

Kasus

Daftar Masalah

sepsis berat ec osteomielitis dan gangren DM pedis

sinistra, bronkopneumonia

DM tipe 2 normoweight gula darah belum terkendali

acute kidney injury ec prerenal dd/acute on CKD ec

diabetic nephropathy

koagulopati suspek DIC

imobilisasi parsial

sindrom dispepsia dengan intake sulit

Kasus

Tatalaksana awal IVFD NS 500cc/6 jam,

O2 3 liter/menit nasal kanul,

Diet cair per NGT 4 x 250cc,

UMU BC cairan ketat setiap 6 jam target balans seimbang,

Kateter urin dengan pemantauan urin output target >0,5 cc/kgBB/menit

Ceftriaxone 2 x 2g IV, levofloxacin 1 x 500mg IV dan metronidazole 3 x 500mg IV.

Drip insulin 1 unit per jam dengan correctional dose.

Ranitidin 2 x 1 amp, domperidon 3 x 10 mg dan paracetamol kalau perlu.

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Follow up

Hari ke 3 debridement dan amputasi

Hari ke 7 kultur pus dan sutum

menunjukkan P.aeruginosa

Hasil kultur resistensi

Bahan : Pus luka operasi

Hasil : Pseudomonas aeruginosa

Piptazo R

Cefuroxim R

Ceftazidim R

Cefotaxim R

Ceftriaxone R

Cefo/Sulb R

Cefepime R

Amikacin R

Gentamycin R

Imipenem R

Doripenem R

Meropenem R

Bahan : Sputum ETT

Hasil : Pseudomonas aeruginosa

Piptazo R

Cefuroxim R

Ceftazidim R

Cefotaxim R

Ceftriaxone R

Cefo/Sulb R

Cefepime R

Amikacin R

Gentamycin R

Imipenem R

Doripenem R

Meropenem R

Diskusi

Apa yang dimaksud dengan PKPD?

Apakah PKPD diperlukan pada penanganan

kasus ini?

Apa yang menjadi parameter dalam PKPD?

Apa yang dimaksud Concentration atau Time

dependent antibiotik

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Outcome in Antimicrobial Usage

Clinical outcome

Microbiological outcome

Consideration When Using

Antimicrobial Agents

Microbiology

Mechanism of action

Antibacterial spectrum

Drug

PK

Absorption

Distribution

Metabolism

Excretion

Optimal dosing

regimen

Concentration

at 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)

Pharamacokinetic : Concentration-Time

PK parameters:

Cmax : peak

C min : trough

Vd

T½ : half life

AUC

Clearence

Protein binding

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Pharmacodynamic : ability to kill

Time dependent

T>MIC

Concentration dependent

Cmax , AUC>MIC

PKPD relationship

PK/PD parameters affecting antibiotic

efficacy in vivo

0

MIC

AUC:MIC

T>MIC

Cmax:MIC Concentration

Time (hours)

PAE

MIC = minimum inhibitory concentration; AUC = area under the curve; T = time;

PAE = post antibiotic effect

Time dependent

T>MIC (CEF)

Concentration dependent

Cmax>MIC (AM)

AUC/MIC (FQ)

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Antibiotic Characteristic base on PKPD C

on

ce

ntr

ati

on

Time (hours)

Cmax = Peak

Cmin = Trough

MIC

T > MIC

Cmax / MIC

Aminoglycosides1,2

Fluoroquinolones1,2

Penicillins1

Cephalosporins1

Carbapenems1

Macrolides1,2

Glycopeptides2

Lincosamides2

AUC / MIC Aminoglycosides2

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>MIC (β-lactams)

0

T>MIC

Concentration

Time (hours)

MIC

Target value: 1. T>MIC in 40%–60% of dosing interval

2. 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

Shorten T>MIC in resistance pathogen

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Cmax = maximum plasma concentration

Cmax:MIC (aminoglycosides)

0

Cmax:MIC

Concentration

Time (hours)

MIC

Target value: Cmax:>8–10 MIC

0

AUC:MIC

Concentration

Time (hours)

MIC

AUC:MIC (fluoroquinolones)

Target value: 1. Gram-positive AUC/MIC >30

2. Gram-negative AUC/MIC >125

Ambrose, et al. Antimicrob Agents Chemother 2001;45:2793–2797;

Forrest, et al. Antimicrob Agents Chemother 1993;37:1073–1081

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Apa yang dimaksud dengan MIC

Apa kaitan PKPD dengan MIC?

Parameters of Antimicrobial Activity

• Potency : MIC

MBC

• Time Course of Activity

Rate of killing

Persistent effects

PAE, PA-SME,

PALE

MIC

Minimum inhibitory concentration

in mg/L or ug/mL

Is the lowest concentration in a series of twofold

concentrations that will inhibit the growth of a

microorganism, as measured by the naked eye.

Convention : series concentration shall contain

the 1 mg/L concentration

ie 0.25 - 0.5 - 1 – 2 – 4 - 8 – 32 -64 - 128

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MIC breakpoint

Value of MIC that correlate with the outcome

MIC break point:

- Clinical breakpoint

- Non species related breakpoint :

PKPD breakpoint, Monte Carlo simulation

- Epidemiological cut off (ECOFF)

Microbiological Lab report

Susceptible/sensitive:

in level of antimicrobial activity associated with

a high likelihood of therapeutic success

Intermediate

uncertain therapeutic effect

Resistant

associated with therapeutic failure

Susceptibility

MIC method

lowest MIC is more sensitive

Zone diameter

wider diameter is more sensitive

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Resistance

Above cut off MIC

Below cut off diameter zone

Probability of failure

MIC and Drug efficacy

MIC is related to potency of the drug

( in vitro )

PK is related to exposure to the bug

( in vivo )

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MIC PK relationship

Relationship between MIC in vitro and

concentration in vivo

Related to :

dosing regimen

drug application

PKPD pada betalactam

PKPD pada aminoglikosida

PKPD glikopeptida (vancomycin)

Relationship between Cmax/MIC and clinical

response in Aminoglycoside treatment

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

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PKPD of Aminoglycoside

AUC/MIC and Peak/MIC is important indices

in determining efficacy

24 hr AUC/MIC >100 along peak/MIC 8-10

require for 90% of efficacy

Efficacy of Tobramycin Monotherapy in

Gram negative Bacilli infections

23 patients with nosocomial pneumonia or IAI

24 hr AUC/MIC > 110 : 80 % clinical cure

24 h AUC/MIC < 110 : 47 % p<0.01

Smith et al. Clin Ther 2001; 23:1231

Pharmacokinetic of betalactam

For beta-lactams in general, the time drug concentration

exceeds the MIC (T>MIC) is predictive of antibacterial activity

Carbapenems have the shortest % T>MIC requirement

compared to penicillins and cephalosporins

% T> MIC*

Bacteriostatic (%)

Bactericidal† (%)

Cephalosporins 35-40 60-70

Penicillins 30 50

Carbapenems 20 40

* 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.

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Improving the PD attainment rate by

prolonging the β-lactam infusion time

30 min 3 hr 4 hr

Increase*

(%)

Meropenem 1 g q8h 77.1 83.8 — +6.7

2 g q8h 84.1 88.1 — +4.7

Pip/tazo 4.5 g q8h 56.4 — 80.7 +24.3

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

*PD attainment

Effect of Doripenem Extended

Infusion on %T > MIC

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

Do

rip

en

em

Co

nc

en

tra

tio

n

(mg

/L)

Time Since Start of Infusion (h)

MIC = 4

32

16

8

4

2

1 0 6 4 2 8 10 12

31% 49%

T>MIC

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Target attaintment when using

difference regimen of doripenem

Clinical Efficacy of Doripenem for

Lower Respiratory Tract Infections

Kapan PKPD diaplikasikan?

Apa yang dimaksud dengan

- intermitten bolus

- extended/prolonged infusion

- continuous infusion

Apa yang menentukan aplikasi obat dengan

metode tersebut?

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Application of PKPD

MDRO

Critically Ill Patients

Immune compromised

Neutropenic patients

Application of PKPD

Time Dependent

Intermitten dosing

Prolong infusion

Continuous infusion

Concentration

Dependent

Once daily dosing

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