Clinical implications of tissue concentrations
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Clinical Issues of PK/PD, ECC, Firenze 2005. Clinical implications of tissue concentrations. Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna, Austria. A ctive antibiotic. Clinical implications of tissue concentrations. Site of infection. Tissue concentrations.

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Clinical implications of tissue concentrations

Clinical Issues of PK/PD, ECC, Firenze 2005

Clinical implications of tissue concentrations

Ursula TheuretzbacherCenter for Anti-Infective Agents, Vienna, Austria


Clinical implications of tissue concentrations1

Active antibiotic

Clinical implications of tissue concentrations

  • Site of infection

  • Tissue concentrations

  • Activity of antibiotic at site of infection

  • Influence on patient outcome?


Site of infection

Picasso

Site of Infection

Cerebrospinal fluid

Middle ear fluid

Maxillarysinus fluid

Bronchial secretion

Epithelial lining fluid

Alveolar macrophages

Urine

Prostate secretion

Extracellular fluid of tissues


Site of infection1

pneumococci, enterobacteria

Legionella, mycobacteria

blood capillary

Mycoplasma,Bordetella

extracellular fluid

cells

Chlamydia, Rickettsia, Ehrlichia

pneumococci, enterobacteria, Haemophilus

Salmonella, Staph. aureus

Shigella, Listeria

Chlamydia, Legionella

intracellular

Site of Infection


Site of infection tissue concentration

blood capillary

homogenates,biopsies

cells

70-80%

  • intravascular

  • extra-, intracellular

  • Bound + free fraction

20-30%

interstitial fluid

high concentrations

low concentrations

  • macrolides

  • fluorquinolones

  • ß-lactams

  • aminoglycosides

Eng`s principle of medical procedures:„The easier it is to do, the harder it is to change.“

Site of Infection – Tissue concentration


Site of infection pk pd

Bacteria:Sensitivity

Body:BarriersDisease

Antibiotic:Protein binding

Site of Infection – PK/PD


Protein binding

Bacteria:Sensitivity

Body:BarriersDisease

Antibiotic:Protein binding

  • Activity

Effect of protein binding on antimicrobial activity against Staphylococcus aureus

65%

CM. Kunin et al. Ann N Y Acad Sci. 1973 (26) 214

Protein Binding

  • Penetration

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


Tissue penetration

Bacteria:Sensitivity

Antibiotic:Protein binding

Body:BarriersDisease

Unbound imipenem mean concentrations in rats: blood, extracellular fluid (muscle, and lung)

S. Marchand et al. AAC 2005 (49) 2356

Tissue Penetration

  • Non-specialized tissues

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


Tissue penetration1

Bacteria:Sensitivity

Antibiotic:Protein binding

Body:BarriersDisease

Meropenem conc. mg/l

hours

Tissue Penetration

  • Specialized tissues

ELF: Meropenem 1g i.v., Allegranzi et al: JAC (2000) 46, 319IF (interstitial fluid, microdialysis): Meropenem 1g i.v., Tomaselli et al: AAC (2004) 48, 2228


Tissue concentrations patients

Bacteria:Sensitivity

Imipenem

Antibiotic:Protein binding

Body:BarriersDisease

plasma

microdialysis

muscle

subcutan. tissue fluid

healthy

patients

Tissue Concentrations - Patients

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


Tissue concentrations patients1

Bacteria:Sensitivity

Antibiotic:Protein binding

Body:BarriersDisease

Tissue concentrations - Patients

Piperacillin 4g

Healthy

ICU-patients

M Brunner et al. Crit. Care Med. 2000, 28:1754


Pk pd patients

Bacteria:Sensitivity

Antibiotic:Protein binding

Body:BarriersDisease

PK/PD – Patients

Killing curves after exposure to levofloxacin at concentrations determined from individual free concentration profiles

MIC = 2 µg/ml

M.A. Zeitlinger et al. AAC 2003 47: 3548


Pk pd outcome

Bacteria:Sensitivity

Antibiotic:Protein binding

Body:BarriersDisease

PK/PD - Outcome

  • Probability of failure was greater when infection was located in tissues with barriers

MIC, trough concentration and ratio in relation to clinical outcome

Piperacillin/Tazobactam, 3 x 4,5g

Sádaba et al, CMI 2004, 10 (11), 990


Tissue concentrations outcome

Bacteria:Sensitivity

Antibiotic:Protein binding

Body:BarriersDisease

Tissue concentrations - Outcome

  • Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. (Joukhadar et al, 2001)


Summary t issue concentration outcome

Summary: Tissue Concentration – Outcome

  • Site of infection  location of antibiotic

  • Precondition for activity

  • Protein binding influences tissue penetration

  • Free blood concentration = concentration in interstitial fluid of tissues (volunteers!)

  • Concentration in interstitial fluid of tissues might be decreased in patients

  • Tissues with penetration barrier


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