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Pharmacokinetics/

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)

Cure Rates at the Test-of-Cure Visit for Microbiologically


Evaluable Adult Patients with Complicated Skin and Skin
Structure Infections
Cured
Pathogen Linezolid Oxacillin/Dicloxacillin
n/N (%) n/N (%)

Staphylococcus aureus 73/83 (88) 72/84 (86)


Methicillin-resistant S. aureus 2/3 (67) 0/0 (-)
Streptococcus agalactiae 6/6 (100) 3/6 (50)
Streptococcus pyogenes 18/26 (69) 21/28 (75)
Kadar antibiotika dalam darah setelah pemberian
teratur tiap 8 jam
Kadar obat dalam darah

Cmax

MTC

Kadar terapetik
MIC

07.00 15.00 23.00 07.00


Waktu pemberian antibiotika

Kadar antibiotika dalam darah setelah pemberian


teratur tiap 8 jam
Kadar obat dalam darah

Cmax

MTC
Tidak ada
obat
di dalam
MIC
darah

7 1300 15 1900 23 700


Waktu pemberian antibiotika
Evaluating antibacterial efficacy using
pharmacokinetics and pharmacodynamics

serum concentration profile


Pharmacokinetics (PK)
penetration to site of infection

susceptibility – MIC (potency)

concentration- vs. time-dependent


Pharmacodynamics (PD)
killing
persistent (post-antibiotic) effects
(PAE)

Jacobs. Clin Microbiol Infect 2001;7:589–96

Pharmacokinetics
Extracellular
compartment
tissues

Oral
ingestion

Blood

Renal GI
Excretion absorption
Tissue Penetration

Landersdorfer et al., Clin Pharmacokinet (2009) 48: 89-124


Pharmacokinetics and Pharmacodynamics of Antibiotics

PK/PD parameter

• T>MIC
• Peak/MIC
• AUC/MIC 24 jam
Pharmacokinetics/pharmacodynamics: predictor for
bacterial eradications

Peak/MIC T > MIC AUC/MIC 24 jam

• Aminoglikosida • Beta laktam • Azitromisin


• Eritromisin • Quinolon
• Clindamisin • Vankomisin
• Linezolid

Pharmacokinetic definitions and alterations in


critical illness
Beta-lactam administration strategies and effect on
pharmacodynamic target

PK/PD and Clinical Outcome


Dose
Pharmacokinetics
• Time course of drug
Drug concentration in blood concentration in the
body

Drug concentration at target site Pharmacodynamics


• Concentration-effect
Efect relationship

Clinical Outcomes
Volume of distribution (Vd)

Clearance (CL)

The primary PK Half-life (T1/2)


parameters of
importance to The peak serum concentration chieved
antibiotics include: by a single dose (Cmax)

The lowest concentration during a


dosing period (Cmin)

The area under the serum


concentration time curve (AUC).

Hydophilic antimicrobials Lipophilic antimicrobials

• Aminoglycosides • Fluoroquinolones
• Beta-lactams • Ketolides
• Carbapenem • Lincosamides
• Cephalosporins • Macrolides
• Penicillins • Metronidazole
• Glycopeptides • Streptogamin
• Lipopeptides • Tetracyclines

• Tissue distribution limited to • Tissue distribution with


the extracellular space intracellular accumulation
• Renal clearance • Hepatic clearance

Sepsis Sepsis

Need for increased or NO Need for


Need for increased NO Need for increased
decreased maintenance maintenance dose
loading dose loading dose
dose adjustments

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

Plasma concentrations vs free, unbound concentrations


in muscle
Current Medical Research & Opinion Volume 26, Number 3 March 2010

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]

Vancomycin Tissue Penetration

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

- Below the mean MICs for many 2.5


strains of staphylococci 2

1.5

0.5

0
Cardiac Valve Myocardium Fat

Tissue

Daschner FD et al. J Antimicrob Chemother. 1987;19:359-362.


Epithelial
CNS: •<10%
lining •18%
fluid3:

Sternal Bone1: • 57%


Lung •17%–24%
Heart Valve4: • 12% tissue2:

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.

Average Steady-State Plasma Linezolid Concentrations After Oral


Administration of 400 or 600 mg Twice Daily

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

Time After Last Dose (hours)

Linezolid Research Update. Denver, Colo: Infectious Diseases Society of America; November 13, 1998.
CNS1: Epithelial
70%* lining fluid4:
450%

Saliva2: Alveolar cells4:


120% 15%

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.

Comparison of Tissue Concentrations


(% Tissue/Serum)

Tissue Vancomycin Linezolid


Bone 7%–13%1 60%8
Cerebral Spinal Fluid 0%–18%2,3 70%9
Epithelial Lining Fluid (Lung) 11%–17%4,5 450%9
Inflammatory Blister Fluid ---- 104%10
Muscle ~30%6 94%8
Peritoneal dialysis fluid ~20%7 61%11

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

1. Limited Vd 1. Large volume


2. Unable to passively diffuse through 2. Free diffuse through plasmatic
plasmatic membrane of eukaryotic cells membrane of eukaryotic cells
3. Inactive against intracellular pathogens 3. Active against intracellular pathogens
4. Eliminated renally as unchanged drug 4. Eliminated by hepatic metabolism
Three important recommendations about
antimicrobial therapy in severe sepsis:
• always begin intravenous antibiotics within the first
hour after severe sepsis and septic shock are
recognized;
• use broad-spectrum agents with good penetration
into the presumed site of infection; and
• reassess the antimicrobial regimen daily to optimize
efficacy, prevent resistance, avoid toxicity and
minimize costs
Conclusion:
• Using the available pooled data we found no
significant mortality benefit of administering
antibiotics within 3 hours of ED triage or within 1
hour of shock recognition in severe sepsis and
septic shock.
• These results suggest that currently recommended
timing metrics as measures of quality of care are
not supported by the available evidence

Pharmacodynamics of a concentration-dependent antimicrobial

1. an elimination half-life of 2 hours


2. administered once daily or in two
divided doses.
3. Under the same total daily dose,
once daily administration ensures
higher C /MIC ratio in presence of
max

equal AUC/MIC ratio.


4. Dotted line a MIC of 2 mg/l.

Federico Pea1 and Pierluigi Viale, 2009


Pharmacodynamics of a time-dependent antimicrobial

1. an elimination half-life of 1 hour


2. administered over 30 minutes or over 3 hours.
3. The extended infusion time increases the time for which the antibiotic concentration
exceeds the minimum inhibitory concentration (t>MIC).
4. Dotted line refers to a MIC of 8 mg/l. Federico Pea1 and Pierluigi Viale, 2009

1. Different administration schedules of 2 g daily vancomycin.


2. in a young male with normal renal function
3. the fixed 30 mg/kg per day
4. 2 or 4 intermittent infusions, or by continuous infusion (CI) after loading (loading dose [LD]).
5. The dotted/dashed line refers to 10 mg/l.
Federico Pea1 and Pierluigi Viale, 2009
Mean Levofloxacin Plasma Mean Levofloxacin Plasma
Concentration vs. Time Profile: Concentration vs. Time Profile:
750 mg 500 mg

Changes in absorption: eg.


Critically ill patient

Factors which decrease


the antibiotic peak Volume of distributiion
concentration:

Penetration to the site of action

Protein binding
Factors which increase the
antibiotic peak
concentration:
Diminished clearance mechanisms
Decreased renal clearance

Factors which increase the


Decreased hepatic clearance
antibiotic half-life

Decreased overall metabolism

Renal replacement therapy

Increased hepatic clearance:


Factors which decrease the
antibiotic half-life
Increased glomerular filtration:

Increased drug metabolism

Antibiotic administration strategies

bacteria can grow again when maintenance of


antimicrobials concentrations plasma trough
fall below the MIC concentrations above
the MIC ought to be
no matter the antibiotics the goal of therapy in
used (time-dependent or daily clinical practice
concentration-dependent). for critically ill patient.
Administration strategies for antibiotics

extended infusion (over 3 to 4 hours).

Continuous infusion.

The problem is the stability at room temperature of the


drugs. Meropenem and imipenem are not good candidates.

some other antibiotics are stable such as


piperacillin/tazobactam; ceftazidime & vancomycin

Defining adequate antimicrobial therapy

the AB should be
after the onset of sepsis (before the
initiated as soon as
Adequate antimicrobial

causative pathogen is known)


possible
the antimicrobial spectrum should be
as therapy is to be
therapy:

broad enough to cover the potential


initiated empirically, causative microorganisms

to maximize microbial killing,

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

• Time course of bacterial killing


• Post-antibiotic effect
• Preclinical infections model