Download Theuretzbacher

14th ISAP Educational Workshop, Nice 2006
Tissue concentrations
Protein binding
Ursula Theuretzbacher
Center for Anti-Infective Agents,
Vienna
Tissue
Tissuepenetration
penetration- -protein
proteinbinding
binding
Int J Clin Pharmacol Ther. 2003 Jun;41(6):267-74.
Pharmacokinetics and tissue penetration of pefloxacin plus metronidazole
after administration as surgical prophylaxis in colorectal surgery. J Antimicrob Chemother. 2001 May;47(5):729-30.
Gascon AR, Gutierrez-Aragon G, Hernandez RM, Errasti J, Pedraz JL. Tissue penetration of a single dose of levofloxacin
intravenously for antibiotic prophylaxis in lung surgery.
J Chemother. 2003 Apr;15(2):139-42.
von Baum H, Bottcher S, Hoffmann H, Sonntag HG.
Ceftriaxone (1 g intravenously) penetration into abdominal tissues
when administered as antibiotic prophylaxis during nephrectomy.
Andrologia. 2003 Oct;35(5):331-5.
Leone M, Albanese J, Tod M, Savelli V, Ragni E, Rossi D, Martin C.
Antibiotic therapy--rationale and evidence for optimal drug
concentrations in prostatic and seminal fluid and in prostatic tissue.
Helicobacter. 2003 Aug;8(4):294-9.
Naber KG, Sorgel F.
Gastric juice, gastric tissue and blood antibiotic concentrations following
omeprazole, amoxicillin and clarithromycin triple therapy.
Int J Clin Pharmacol Ther. 2003 Jun;41(6):267-74.
Nakamura M, Spiller RC, Barrett DA, Wibawa JI, Kumagai N, Tsuchimoto K,
Pharmacokinetics and tissue penetration of
Tanaka T.
pefloxacin plus metronidazole after administration
as surgical prophylaxis in colorectal surgery.
J Chemother. 2003 Apr;15(2):139-42.
Gascon AR, Gutierrez-Aragon G, Hernandez RM,
Errasti J, Pedraz JL.
Ceftriaxone (1 g intravenously) penetration into abdominal tissues when
administered as antibiotic prophylaxis during nephrectomy.
Leone M, Albanese J, Tod M, Savelli V, Ragni E, Rossi D, Martin C.
Tissue
Eng`s principle of medical procedures:
„The easier it is to do, the harder it is
to change.“
blood capillary
70-80%
homogenates,
biopsies
cells
•intravascular
•extra-, intracellular
20-30%
interstitial fluid
•Bound + free fraction
high concentrations
macrolides
fluorquinolones
low concentrations
ß-lactams
aminoglycosides
Tissue penetration - protein binding
Where is the
antibiotic?
Where is the
pathogen?
Activity!
Specimen?
Active concentration
(protein binding!)
Where is the pathogen?
blood capillary
extracellular fluid
cells
Salmonella,
Staph. aureus
Shigella,
Listeria
Chlamydia,
Legionella
intracellular
Site of Infection
Pneumonia
ELF, AM, blood,
microdialysate
KU Medical Center
Bronchitis
bronchial secretions
Sinusitis
sinus secretions
Otitis media
middle ear fluid
Barrier
Concentrations In The Lung
Zeitlinger et al. AAPS Journal. 2005; 7(3): E600-E608
Tissue concentration: pulmonary
Telithromycin, pulmonary disposition
800mg once daily, 5 days
90
Total concentrations (g/ml)
80
70
60
2h
8h
24h
48h
50
40
30
20
10
0
1 0,6 0,06 0
Plasma
Muller-Serieys et al. AAC 2001, 45 (11)
ELF
AM
Tissue concentration: middle ear
Acute otitis media, concentrations in middle ear fluid
Ceftibuten: 9mg/kg
Cefixime: 8mg/kg
Azithromycin: 10mg/kg
g/ml
14
cellfree
12
10
4h
12 h
24 h
with
cells
8
6
with
cells
4
2
cellfree
with
cells
0
Ceftibuten
F Scaglione et al. Br J Clin Pharmacol 1999, 47 (3)
Cefixime
Azithromycin
cellfree
Tissue concentrations
Tissue specific
brain, prostate, muscles, lung….
Compartment specific
extracellular
intracellular
intracellular
compartments
Patient specific
 Activity
Tissue concentrations - patients
Imipenem 500mg
Microdialysis in muscle, subcutaneous tissue
healthy
patients
I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325
Concentrations In The Lung – Cardiac Surgery
Levofloxacin 500 mg
Microdialysis in lung
Concentration in plasma
Concentration in pulmonary interstitial fluid
PK/PD
unbound AUCtissue/MIC ratio  30-40
Hutschala D et al: AAC 2005, 49: 5107
Lung:
unbound AUCtissue/MIC ratio  1-4 for
pseudomonas
Concentration at site of infection  activity
Ciprofloxacin 200 mg
Increase of Microcirculatory Blood Flow
Interstitial fluid of subcutaneous
adipose tissue (warmed +
reference tissue)
Joukhadar C et al: AAC 2005, 49: 4149
Time-kill curves for P. aeruginosa
(MIC 0.12, 0.5, 2 mg/l)
Tissue concentration: middle ear
Haemophilus influenzae
amox/clav
cefaclor
Concentration in middle ear
(mean, g/ml)
Bacteriologic eradication
(after 4-5 days of therapy)
9,5
87%
(amoxycillin 25 mg/kg dose, 3h)
(amoxycillin/clavulanic acid
45/6,4mg/kg/day)
5,1
48%
(20mg/kg single dose, 2h)
3,5
azithromycin
MIC
2
s
2
s
47% (39%)
(10mg/kg day 1, 5mg/kg days 2-5)
s: NCCLS susceptible
Placebo!
R Dagan et al: AAC 2000, 44 (1)
R Dagan et al: Pediatr Inf Dis J 2000, 19 (2)
DM. Canafax et al: Pediatr Inf Dis J 1998, 17 (2)
T Eden et al: Scand J Infect Dis 1983, Suppl, 39
JO Klein, CID 1994,19 (5)
0,5 s
Protein binding
non-specialized tissues
serum
specialized tissues
interstitial
fluid
bound
bound
free
drug
equilibrium
• small reservoirs
• large reservoirs
free
drug
transport pump
diffusional
barriers
Protein binding
affects
Distribution
Tissue penetration
Clearance
Interactions
Activity
Ertapenem
Relationships between EC50 and
% human serum for E. cloacae (•)
and S. aureus ()
DE Nix et al. AAC 2004 (48) 3419
Protein binding: Effect on Penetration of ß-Lactams
% Penetration of total drug (AUC lymph/AUC plasma
into Rabbit Peripheral Lymph
Correlation between protein binding and penetration
100
75
50
25
25
50
Plasma binding %
G Woodnutt et al. AAC 1995, 39 (12)
75
100
Protein Binding: Cefotaxime - Ceftriaxone
60
g/ml
50
Cefotaxime 1g iv
serum: total
40
serum free
pleural fluid: total
30
35%
pleural fluid: free
20
10
0
100
0
1
2
0
1
2
90
3
4
5
6
3
4
5
6
Ceftriaxone 1g iv
80
70
60
95%
50
40
30
20
10
0
F Scaglione et al. JAC 1990, 26, Suppl A
h
Protein binding
Telithromycin
Mean time-versus-concentration profiles
of total and free telithromycin in plasma,
muscle, and subcutis (800 mg p.o.)
R. Gattringer et al. AAC 2004 (48) 4650
Protein binding
>90%
>70%
Oxacillin, ceftriaxone,
ertapenem, teicoplanin,
daptomycin, televancin,
fusidic acid, rifapentine
Cefazolin, rifampicin,
oritavancin
>30%
>10%
Penicillin G,
cefixime, cefotaxime,
erythromycin, clarithromycin,
azithromycin, telithromycin
vancomycin, linezolid
Amoxicillin, piperacillin
cefpodoxime, cefuroxime,
ceftazidime, imipenem
ciprofloxacin, levofloxacin,
gatifloxacin, metronidazole
<10%
Meropenem, doripenem,
aminoglycosides, fosfomycin
Summary: tissue concentration – protein binding
Tissue penetration:
• Precondition for activity
• Site of infection  location of antibiotic
• Don`t mix separated pharmacokinetic compartments
(homogenates!), results may be misleading!
Protein binding:
• Free drug is active
• Highly protein bound drugs have reduced antibacterial effect
in vitro (with albumin)
• Don’t correlate MIC (measured in protein-free media) with
total concentrations
• Protein binding influences tissue penetration
• Drugs with high protein binding are not generally less
clinically active
Whitehead`s rule:
Seek simplicity, and distrust it.
Take home message:
Consider free levels
Distrust tissue homogenates
Enjoy the meeting