1. Clinical implications of tissue concentrations Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna, Austria Clinical Issues of PK/PD, ECC, Firenze 2005

2. Clinical implications of tissue concentrations Active antibiotic Site of infection Tissue concentrations Activity of antibiotic at site of infection Influence on patient outcome?

3. Site of Infection Picasso Middle ear fluid Maxillary sinus fluid Cerebrospinal fluid Bronchial secretion Epithelial lining fluid Alveolar macrophages Urine Extracellular fluid of tissues Prostate secretion

4. Site of Infection blood capillary extracellular fluid cells pneumococci, enterobacteria pneumococci, enterobacteria, Haemophilus Chlamydia, Rickettsia, Ehrlichia Legionella, mycobacteria Mycoplasma, Bordetella Salmonella, Staph. aureus Shigella, Listeria Chlamydia, Legionella intracellular

5. blood capillary interstitial fluid cells Site of Infection – Tissue concentration 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.“

6. Site of Infection – PK/PD Body : Barriers Disease Antibiotic : Protein binding Bacteria : Sensitivity

7. 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.) Penetration CM. Kunin et al. Ann N Y Acad Sci. 1973 (26) 214 Activity Effect of protein binding on antimicrobial activity against Staphylococcus aureus Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity 65%

8. Tissue Penetration 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.) Non-specialized tissues Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity Unbound imipenem mean concentrations in rats: blood, extracellular fluid (muscle, and lung) S. Marchand et al. AAC 2005 (49) 2356

9. Tissue Penetration Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity Specialized tissues hours Meropenem conc. mg/l ELF: Meropenem 1g i.v., Allegranzi et al: JAC (2000) 46, 319 IF (interstitial fluid, microdialysis): Meropenem 1g i.v., Tomaselli et al: AAC (2004) 48, 2228

10. Tissue Concentrations - Patients I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325 plasma muscle subcutan. tissue fluid healthypatients microdialysis Imipenem Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity

11. Tissue concentrations - Patients M Brunner et al. Crit. Care Med. 2000, 28:1754 ICU-patientsHealthy Piperacillin 4g Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity

12. PK/PD – Patients MIC = 2 µg/ml M.A. Zeitlinger et al. AAC 2003 47: 3548 Killing curves after exposure to levofloxacin at concentrations determined from individual free concentration profiles Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity

13. PK/PD - Outcome Probability of failure was greater when infection was located in tissues with barriers Sádaba et al, CMI 2004, 10 (11), 990 Piperacillin/Tazobactam, 3 x 4,5g MIC, trough concentration and ratio in relation to clinical outcome Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity

14. Tissue concentrations - Outcome Impaired target site penetration of beta- lactams may account for therapeutic failure in patients with septic shock. (Joukhadar et al, 2001) Body: Barriers Disease Antibiotic: Protein binding Bacteria: Sensitivity

15. 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