Tissue concentrationsProtein binding

Ursula TheuretzbacherCenter for Anti-Infective Agents,

Vienna

12th ISAP Educational Workshop, Copenhagen 2005

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

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!??

Tissue penetration - protein binding

Where is the Where is the pathogen ?pathogen ?

Where is the Where is the antibiotic ?antibiotic ?

Active concentration(protein binding!)

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

blood capillary

interstitial fluid

cellscells

Where is the antibiotic?

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.“

Site of Infection

Pneumonia

ELF, AM, blood

Bronchitis

bronchial secretionsSinusitis

sinus secretions

Otitis media

middle ear fluid

BarrierBarrier

KU Medical Center

Tissue specificbrain, prostate, muscles, lung….

Activity

Tissue concentrations

Patient specific

Compartment specific

extracellularintracellular

intracellular compartments

plas

ma

mus

cle

subc

utan

. t.

healthy patients

microdialys

is

I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325

Imipenem

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)

Tissue concentration: pulmonary

K Rodvold et al. AAC, 1997, 41 (6)

0,01

0,1

1

10

100

1000

4 8 12 24

Clari: plasma Azi: plasma Clari: ELF

Azi: ELF Clari: AM Azi: AM

g/ml

h241284

Clarithromycin: 2x 500mg, 4 days

Azithromycin: 1x 500mg /1x 250mg, 4 days

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

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

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

Protein binding

affectsdistribution

tissue penetration

clearance

interactions

S Tawara et al. AAC 1992, 36 (1)

activity!

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 %

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

Protein binding

R. Gattringer et al. AAC 2004 (48) 4650

Relationships between EC50 and % human serum for E. cloacae (•) and S. aureus ()

DE Nix et al. AAC 2004 (48) 3419

Mean time-versus-concentration profiles of total and free telithromycin in plasma, muscle, and subcutis (800 mg p.o.)

ErtapenemTelithromycin

Protein binding

D. Andes: Infect Dis Clin N Am 2003 (17) 635

Azoles

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

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

Take home message:

Consider free levels

Distrust tissue homogenates

Enjoy the meeting

Whitehead`s rule:Seek simplicity, and distrust it.