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Iwan - PK PD of antibiotics-PPRA 28 Juli, 2018-1 PDF
Iwan - PK PD of antibiotics-PPRA 28 Juli, 2018-1 PDF
Pharmacodynamic consideration
in the Use of Antibiotics
Iwan Dwiprahasto
Department of Pharmacology & Therapy, Faculty of Medicine, UGM
Curriculum vitae
Nama : Prof. dr. Iwan Dwiprahasto, MMedSc, PhD
Riwayat pendidikan
Dokter, FK UGM tahun 1987
S-2: MMedSc Newcastle University Australia, 1993
S-3: PhD, London School of Hygiene & Tropical Med, England, 2000
Jabatan:
1. Ketua Komite Nasional (KOMNAS) Fornas (Formularium Nasional), Kemkes RI
2. Ketua, Komite Nasional (KOMNAS) DOEN (Daftar Obat Esensial Nasional), Kemkes RI
3. Ketua, Komite Nasional (KOMNAS) Formularium Haji, Kemkes RI
4. Wakil Ketua, Komite Nasional (KOMNAS) Kompendium Alat Kesehatan (Kemkes RI)
5. Komite Nasional (KOMNAS) Penilai Obat Jadi Badan POM RI
6. Komite Nasional (KOMNAS) Informatorium Obat Nasional Indonesia (IONI)
7. Komite Nasional (KOMNAS) Obat Tradisional dan Suplemen Makanan
8. Komite Nasional (KOMNAS) Penilaian Teknologi Kesehatan, Kemkes RI
9. Ketua, Penyusun Formularium Obat Inhealth Indonesia
10. Dewan Pertimbangan Medik (Medical Advisory Board) BPJS Pusat
11. Dewan Pertimbangan Medik (Medical Advisory Board) Inhealth Indonesia
12. Board of Governor, International Clinical Epidemiology Network (INCLEN)
Antibiotics in the Real World
To reduce mortality
of septic patients
Antimicrobial
Antibiotics are used resistance
inappropriately
Very slow
development of
Antibiotics always antibiotics
needed
Pharmacokinetics-
pharmacodynamics
High incidence of
sepsis
Antibiotics: Relative Efficacy
MEROPENEM IMIPENEM-CILASTATIN
MICROORGANISMS*
(%)§ (%)§
Gram-
Gram-positive aerobes
Staphylococcus aureus,
methicillin susceptible 93 84
Strep. pyogenes(Group A) 90 88
Strep agalactiae(Group B) 71 84
Enterococcus faecalis 75 70
Strept viridans Group, nos 92 83
Gram-
Gram-negative aerobes
Escherichia coli 80 71
Pseudomonas aeruginosa 73 87
Proteus mirabilis 85 86
Anaerobes
Bacteroides fragilis 91 90
Efficacy of Meropenem in Skin and Skin Structure
infection
SUCCESS RATE*
Meropenem Imipenem-cilastatin
Population
N†/N‡ (%) N†/N‡ (%)
Total 225/261 (86) 238/287 (83)
Diabetes mellitus 83/97 (86) 76/105 (72)
No diabetes mellitus 142/164 (87) 162/182 (89)
< 65 years of age 190/218 (87) 205/241 (85)
≥ 65 years of age 35/43 (81) 33/46 (72)
Men 130/148 (88) 137/172 (80)
Women 95/113 (84) 101/115 (88)
Cmax
MTC
Kadar terapetik
MIC
Cmax
MTC
Tidak ada
obat
di dalam
MIC
darah
Pharmacokinetics
Extracellular
compartment
tissues
Oral
ingestion
Blood
Renal GI
Excretion absorption
Tissue Penetration
PK/PD parameter
• T>MIC
• Peak/MIC
• AUC/MIC 24 jam
Pharmacokinetics/pharmacodynamics: predictor for
bacterial eradications
Clinical Outcomes
Volume of distribution (Vd)
Clearance (CL)
• Aminoglycosides • Fluoroquinolones
• Beta-lactams • Ketolides
• Carbapenem • Lincosamides
• Cephalosporins • Macrolides
• Penicillins • Metronidazole
• Glycopeptides • Streptogamin
• Lipopeptides • Tetracyclines
Sepsis Sepsis
Physicochemical properties of antimicrobials and dosage requirements in the presence of severe sepsis. *Need for dose reductions only indicated in case of severe hepatic failure
Plasma concentrations vs free, unbound concentrations
in muscle
Current Medical Research & Opinion Volume 26, Number 3 March 2010
Levofloxacin PK/PD correlations
134 hospitalized patients with respiratory tract, skin or complicated urinary
tract infections treated with 500 mg qd for 5–14 days
100
100
90 Clinical outcome
80
Success
No. of patients
70
60
Failure
50
40
30 23
20
10 4 3 3 1
0
AUC:MIC <25 AUC:MIC 25–100 AUC:MIC >100
Peak:MIC <3 Peak:MIC 3–12 Peak:MIC >12
Clinical
failure rate 43% 11.5% 1%
Jacobs. Clin Microbiol Infect 2001;7:589–96
[Adapted from Preston et al. JAMA 1998;279:125–9]
4.5
33 open-heart surgery patients, 4
mean vancomycin
3.5 Tissue Level (mg/L)
concentrations after 15 mg/kg
Level (mg/L)
IV dose 3
1.5
0.5
0
Cardiac Valve Myocardium Fat
Tissue
Vancomycin Penetration
Fat4 • 14%
Bone5: • 7%–13%
Muscle4 • 9%
1. Massias L et al. Antimicrob Agents Chemother. 1992;36:2539-2541; 2. Cruciani M et al. J Antimicrob Chemother. 1996;38:865-869. 3. Lamer C et al.
Antimicrob Agents Chemother. 1993;37:281-286; 4. Daschner FD et al. J Antimicrob Chemother. 1987;19:359-362; 5. Graziani AL et al. Antimicrob Agents
Chemother. 1988;32:1320-1322.
20
18
Linezolid concentration (μg/mL)
16 600 mg BID
14 400 mg BID
12 MIC-90 Staph
10 MIC-90 Entero
8 MIC-90 Strep
6
4
2
0
0 5 10 15 20
Linezolid Research Update. Denver, Colo: Infectious Diseases Society of America; November 13, 1998.
CNS1: Epithelial
70%* lining fluid4:
450%
Linezolid Penetration
Sweat2:
Bone3: 55%
40%–60% Skin Blister Fluid5:
100%
1. Cottagnound et al. J Antimicrob Chemother. 2000;46:981-985; 2. ZYVOX® (linezolid injection, tablets, and oral suspension) [package insert]. Kalamazoo,
Mich: Pharmacia & Upjohn, a Pfizer Company; revised 2003; 3. Lovering AM et al. J Antimicrob Chemother. 2002, 50:73-77; 4. Conte JE et al. Antimicrob
Agents Chemother. 2002;46:1475-1480; 5. Gee T. Antimicrob Agents Chemother. 2001;45:1843-1846.
1. Graziani AL et al. Antimicrob Agents Chemother. 1988;32:1320-1322; 2. Matzke et al. Clin Pharmacokinet. 1986;11:257-282; 3. Albanese J et al.
Antimicrob Agents Chemother. 2000;44:1356-1358; 4. Georges H et al. Eur J Clin Microbiol Infect Dis. 1997;16:385-388; 5. Lamer C et al. Antimicrob
Agents Chemother. 1993;37:281-286; 6. Daschner FD et al. J Antimicrob Chemother. 1987;20:776-782; 7. Blevins RD et al. Antimicrob Agents
Chemother. 1984;25:603-606; 8. Lovering AM et al. J Antimicrob Chemother. 2002;50:73-77; 9. Conte JE et al. Antimicrob Agents Chemother.
2002;46:1475-1480; 10. Gee T et al. Antimicrob Agents Chemother. 2001;45:1843-1846; 11. Gendjar SR et al. 2001 ASN/ISN World Congress of
Nephrology; 2001; San Francisco, Calif. Abstract 550865.
Classification of antimicrobials according to their
solubility and PK/PD properties
Hydrophilic antibiotics Lipopophilic antibiotics
Beta lactams Macrolides
Glycopeptide Fluoroquinolones
Aminoglycoside Tetracyclines
Chloramphenicol
Rifampicin
Linezolide
Protein binding
Factors which increase the
antibiotic peak
concentration:
Diminished clearance mechanisms
Decreased renal clearance
Continuous infusion.
the AB should be
after the onset of sepsis (before the
initiated as soon as
Adequate antimicrobial
appropriate
To minimize risk of antimicrobial
antimicrobial dosing is resistance,
required
avoid concentration-related adverse
drug reactions
Approach to the infected/sepsis patient for the provision of
optimal antibiotic therapy
Pharmacokinetic
• Relative solubility
• Protein binding
• Clearance mechanism
Clinical consideration
Clinical trial
• Site of infection
data
Infected • Severity of Illness
• Body composition
Optimal antibiotic
dosing regimen
patient • Likely pathogen Modeling &
• Local Resistance pattern simulation
Pharmacodynamic