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Clinical implications of tissue concentrations Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna, Austria Clinical Issues of PK/PD, ECC, Firenze 2005
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Clinical implications of tissue concentrations Active antibiotic Site of infection Tissue concentrations Activity of antibiotic at site of infection Influence on patient outcome?
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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
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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
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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.“
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Site of Infection – PK/PD Body : Barriers Disease Antibiotic : Protein binding Bacteria : Sensitivity
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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.) 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%
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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
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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
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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
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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
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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
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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
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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
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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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