t issue concentrations protein binding
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1 4 th ISAP Educational Workshop, Nice 2006. T issue concentrations Protein binding. Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna. High tissue concentrations!??. Tissue penetration - protein binding. Tissue penetration - protein binding. - PowerPoint PPT PresentationTRANSCRIPT
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Tissue concentrationsProtein binding
Ursula TheuretzbacherCenter for Anti-Infective Agents,
Vienna
14th ISAP Educational Workshop, Nice 2006
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J Chemother. 2003 Apr;15(2):139-42.
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.
Helicobacter. 2003 Aug;8(4):294-9.
Gastric juice, gastric tissue and blood antibiotic concentrations following omeprazole, amoxicillin and clarithromycin triple therapy.
Nakamura M, Spiller RC, Barrett DA, Wibawa JI, Kumagai N, Tsuchimoto K, Tanaka T.
Tissue penetration - protein binding Tissue penetration - protein binding Tissue penetration - protein binding
J Chemother. 2003 Apr;15(2):139-42.
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.
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.
Gascon AR, Gutierrez-Aragon G, Hernandez RM, Errasti J, Pedraz JL.
J Antimicrob Chemother. 2001 May;47(5):729-30. Tissue penetration of a single dose of levofloxacin intravenously for antibiotic prophylaxis in lung surgery.
von Baum H, Bottcher S, Hoffmann H, Sonntag HG.
Andrologia. 2003 Oct;35(5):331-5.
Antibiotic therapy--rationale and evidence for optimal drug concentrations in prostatic and seminal fluid and in prostatic tissue.
Naber KG, Sorgel F.
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.
Gascon AR, Gutierrez-Aragon G, Hernandez RM, Errasti J, Pedraz JL.
High tissue High tissue
concentrations!??concentrations!??
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blood capillary
interstitial fluid
cells
Tissue
macrolides
fluorquinolones
high concentrations
ß-lactams
aminoglycosides
low concentrations
70-80%
20-30%
homogenates,biopsies
•intravascular
•extra-, intracellular
•Bound + free fraction
Eng`s principle of medical procedures:„The easier it is to do, the harder it is to change.“
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Tissue penetration - protein binding
Where is the Where is the antibiotic?antibiotic?
Where is the Where is the pathogen?pathogen?
Active concentration(protein binding!)
Specimen?
Activity!
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Where is the pathogen?
blood capillary
extracellularextracellular fluid fluid
cellscells
pneumococci, enterobacteria
pneu
moc
occi,
ente
roba
cteria
,
Haem
ophil
us
Chlamydia, Rickettsia, Ehrlichia
Legionella,
mycobacteria
Mycoplasma,
Bordetella
Salmonella, Staph. aureus
Shigella, Listeria Chlamydia,
Legionellaintracellularintracellular
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Site of Infection
Pneumonia
ELF, AM, blood, microdialysate
Bronchitis
bronchial secretionsSinusitis
sinus secretions
Otitis media
middle ear fluid
BarrierBarrier
KU Medical Center
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Concentrations In The Lung
Zeitlinger et al. AAPS Journal. 2005; 7(3): E600-E608
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0
10
20
30
40
50
60
70
80
90
Plasma ELF AM
800mg once daily, 5 days
2h
8h
24h
48h
Tissue concentration: pulmonary
Telithromycin, pulmonary disposition
1 0,6 0,06 0
Muller-Serieys et al. AAC 2001, 45 (11)
Tot
al c
once
ntr
atio
ns
(g
/ml)
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Tissue concentration: middle ear
Acute otitis media, concentrations in middle ear fluid
0
2
4
6
8
10
12
14
Ceftibuten: 9mg/kg Cefixime: 8mg/kg
Azithromycin: 10mg/kg
4 h
12 h
24 h
g/ml
Ceftibuten
with cells
F Scaglione et al. Br J Clin Pharmacol 1999, 47 (3)
Cefixime
with cells
Azithromycin
with cells cell-
free
cell-free
cell-free
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Tissue specificbrain, prostate, muscles, lung….
Activity
Tissue concentrations
Patient specific
Compartment specific
extracellularintracellular
intracellular compartments
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Tissue concentrations - patients
healthy
plas
ma
mus
cle
subc
utan
. t.
patients
I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325
Imipenem 500mgMicrodialysis in muscle, subcutaneous tissue
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Levofloxacin 500 mgMicrodialysis in lung
Hutschala D et al: AAC 2005, 49: 5107
Concentration in plasma
Concentration in pulmonary interstitial fluid
Concentrations In The Lung – Cardiac Surgery
Lung:unbound AUCtissue/MIC ratio 1-4 for pseudomonas
unbound AUCtissue/MIC ratio 30-40
PK/PD
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Concentration at site of infection activity
Joukhadar C et al: AAC 2005, 49: 4149
Time-kill curves for P. aeruginosa (MIC 0.12, 0.5, 2 mg/l)
Interstitial fluid of subcutaneous adipose tissue (warmed + reference tissue)
Ciprofloxacin 200 mg
Increase of Microcirculatory Blood Flow
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Concentration in middle ear (mean, g/ml)
Bacteriologic eradication
(after 4-5 days of therapy)
9,5 (amoxycillin 25 mg/kg dose, 3h)
87%(amoxycillin/clavulanic acid 45/6,4mg/kg/day)
5,1 (20mg/kg single dose, 2h)
48%
3,5 (10mg/kg day 1, 5mg/kg days 2-5)
47% (39%)
Tissue concentration: middle ear
Haemophilus influenzae
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)
Placebo!
MIC
ss
ss
ss
ss: NCCLS susceptible
0,5
2
2
amox/clav
cefaclor
azithromycin
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Protein binding
• small reservoirs• large reservoirs
free drug
free drug
bound
bound
serum interstitial fluid
non-specialized tissues specialized tissues
diffusional barriers
transport pump
equilibrium
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Protein binding
affectsDistribution
Tissue penetration
Clearance
Interactions
Ertapenem
Relationships between EC50 and % human serum for E. cloacae (•) and S. aureus ()
DE Nix et al. AAC 2004 (48) 3419
Activity
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Protein binding: Effect on Penetration of ß-Lactams into Rabbit Peripheral Lymph
75
25
% P
enet
ratio
n o
f to
tal d
rug
(AU
C ly
mp
h/A
UC
pla
sma
50 100
Correlation between protein binding and penetration
G Woodnutt et al. AAC 1995, 39 (12)
25 75
50
100
Plasma binding %
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Protein Binding: Cefotaxime - Ceftriaxone
Cefotaxime 1g iv
0
10
20
30
40
50
60
0 1 2 3 4 5 6
serum: total
serum free
pleural fluid: total
pleural fluid: free
g/ml
35%
95%
F Scaglione et al. JAC 1990, 26, Suppl A
Ceftriaxone 1g iv
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 h
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Protein binding
R. Gattringer et al. AAC 2004 (48) 4650
Mean time-versus-concentration profiles of total and free telithromycin in plasma, muscle, and subcutis (800 mg p.o.)
Telithromycin
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Protein binding
>90%>90%Oxacillin, ceftriaxone, Oxacillin, ceftriaxone, ertapenem, teicoplanin, ertapenem, teicoplanin, daptomycin, televancin, daptomycin, televancin, fusidic acid, rifapentinefusidic acid, rifapentine
>70%Cefazolin, rifampicin, oritavancin
>30%Penicillin G, cefixime, cefotaxime,erythromycin, clarithromycin, azithromycin, telithromycinvancomycin, linezolid
<10%Meropenem, doripenem, aminoglycosides, fosfomycin
>10%Amoxicillin, piperacillincefpodoxime, cefuroxime, ceftazidime, imipenemciprofloxacin, levofloxacin, gatifloxacin, metronidazole
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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
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Take home message:
Consider free levels
Distrust tissue homogenates
Whitehead`s rule:Seek simplicity, and distrust it.
Enjoy the meeting