Transcript Antibiotic
Clinical Issues of PK/PD, ECC, Firenze 2005 Clinical implications of tissue concentrations Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna, Austria Clinical implications of tissue concentrations Active antibiotic Site of infection Tissue concentrations Activity of antibiotic at site of infection Influence on patient outcome? Site of Infection Cerebrospinal fluid Middle ear fluid Maxillary sinus fluid Bronchial secretion Epithelial lining fluid Alveolar macrophages Urine Prostate secretion Picasso Extracellular fluid of tissues Site of Infection blood capillary extracellular fluid cells Salmonella, Staph. aureus Shigella, Listeria Chlamydia, Legionella intracellular Site of Infection – Tissue concentration blood capillary 70-80% Eng`s principle of medical procedures: „The easier it is to do, the harder it is to change.“ homogenates, biopsies cells •intravascular •extra-, intracellular 20-30% interstitial fluid •Bound + free fraction high concentrations macrolides fluorquinolones low concentrations ß-lactams aminoglycosides Site of Infection – PK/PD Bacteria: Sensitivity Antibiotic: Body: Protein binding Barriers Disease Bacteria: Sensitivity Protein Binding Antibiotic: Protein binding Penetration Mean time-versus-concentration profiles of total and free telithromycin in plasma, muscle, and subcutis (800 mg p.o.) Body: Barriers Disease Activity Effect of protein binding on antimicrobial activity against Staphylococcus aureus 65% R. Gattringer et al. AAC 2004 (48) 4650 CM. Kunin et al. Ann N Y Acad Sci. 1973 (26) 214 Bacteria: Sensitivity Tissue Penetration Antibiotic: Protein binding Body: Barriers Disease Non-specialized tissues Mean time-versus-concentration profiles of total and free telithromycin in plasma, muscle, and subcutis (800 mg p.o.) Unbound imipenem mean concentrations in rats: blood, extracellular fluid (muscle, and lung) S. Marchand et al. AAC 2005 (49) 2356 R. Gattringer et al. AAC 2004 (48) 4650 Bacteria: Sensitivity Tissue Penetration Antibiotic: Protein binding Specialized tissues 45 Meropenem conc. mg/l 40 35 30 Plasma (ELF) ELF Plasma (IF) IF 25 20 15 10 5 0 0,5 1 2 4 6 hours 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 Body: Barriers Disease Tissue Concentrations - Patients Imipenem healthy patients I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325 Bacteria: Sensitivity Antibiotic: Protein binding Body: Barriers Disease Bacteria: Sensitivity Tissue concentrations - Patients Antibiotic: Protein binding Piperacillin 4g Healthy M Brunner et al. Crit. Care Med. 2000, 28:1754 ICU-patients Body: Barriers Disease 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 Bacteria: Sensitivity Antibiotic: Protein binding Body: Barriers Disease PK/PD - Outcome Bacteria: Sensitivity Antibiotic: Protein binding 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 Body: Barriers Disease Bacteria: Sensitivity Tissue concentrations - Outcome Antibiotic: Protein binding Impaired target site penetration of betalactams may account for therapeutic failure in patients with septic shock. (Joukhadar et al, 2001) Body: Barriers Disease 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