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Clinical implications of tissue concentrations

Clinical implications of tissue concentrations

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Clinical implications of tissue concentrations

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

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

  3. 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

  4. 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

  5. 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

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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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)

  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