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T issue concentrations Protein binding

1 4 th ISAP Educational Workshop, Nice 2006. T issue concentrations Protein binding. Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna. High tissue concentrations!??. Tissue penetration - protein binding. Tissue penetration - protein binding.

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T issue concentrations Protein binding

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  1. 14th ISAP Educational Workshop, Nice 2006 Tissue concentrationsProtein binding Ursula TheuretzbacherCenter for Anti-Infective Agents, Vienna

  2. High tissue concentrations!?? Tissue penetration - protein binding Tissue penetration - protein binding Tissue penetration - protein binding Int J Clin Pharmacol Ther. 2003 Jun;41(6):267-74. Pharmacokinetics and tissue penetration of pefloxacin plus metronidazole after administration as surgical prophylaxis in colorectal surgery.Gascon AR, Gutierrez-Aragon G, Hernandez RM, Errasti J, Pedraz JL. J Antimicrob Chemother. 2001 May;47(5):729-30. Tissue penetration of a single dose of levofloxacin intravenously for antibiotic prophylaxis in lung surgery.von Baum H, Bottcher S, Hoffmann H, Sonntag HG. J Chemother. 2003 Apr;15(2):139-42. Ceftriaxone (1 g intravenously) penetration into abdominal tissues when administered as antibiotic prophylaxis during nephrectomy.Leone M, Albanese J, Tod M, Savelli V, Ragni E, Rossi D, Martin C. Andrologia. 2003 Oct;35(5):331-5. Antibiotic therapy--rationale and evidence for optimal drug concentrations in prostatic and seminal fluid and in prostatic tissue.Naber KG, Sorgel F. Helicobacter. 2003 Aug;8(4):294-9. Gastric juice, gastric tissue and blood antibiotic concentrations following omeprazole, amoxicillin and clarithromycin triple therapy.Nakamura M, Spiller RC, Barrett DA, Wibawa JI, Kumagai N, Tsuchimoto K, Tanaka T. Int J Clin Pharmacol Ther. 2003 Jun;41(6):267-74. Pharmacokinetics and tissue penetration of pefloxacin plus metronidazole after administration as surgical prophylaxis in colorectal surgery.Gascon AR, Gutierrez-Aragon G, Hernandez RM, Errasti J, Pedraz JL. J Chemother. 2003 Apr;15(2):139-42. Ceftriaxone (1 g intravenously) penetration into abdominal tissues when administered as antibiotic prophylaxis during nephrectomy.Leone M, Albanese J, Tod M, Savelli V, Ragni E, Rossi D, Martin C.

  3. 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.“ Tissue

  4. Where is the pathogen? Activity! Specimen? Active concentration(protein binding!) Tissue penetration - protein binding Where is the antibiotic?

  5. 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 Where is the pathogen?

  6. KU Medical Center • Bronchitis • bronchial secretions • Sinusitis • sinus secretions • Otitis media • middle ear fluid Barrier Site of Infection • Pneumonia • ELF, AM, blood, microdialysate

  7. Concentrations In The Lung Zeitlinger et al. AAPS Journal.  2005; 7(3): E600-E608

  8. Tissue concentration: pulmonary Telithromycin, pulmonary disposition Total concentrations (g/ml) 1 0,6 0,06 0 Muller-Serieys et al. AAC 2001, 45 (11)

  9. Ceftibuten: 9mg/kg Cefixime: 8mg/kg Azithromycin: 10mg/kg cell-free 4 h withcells 12 h 24 h cell-free withcells withcells cell-free Ceftibuten Cefixime Azithromycin Tissue concentration: middle ear Acute otitis media, concentrations in middle ear fluid g/ml 14 12 10 8 6 4 2 0 • F Scaglioneet al. Br J Clin Pharmacol 1999, 47 (3)

  10. Compartment specific extracellularintracellular intracellular compartments Tissue concentrations • Tissue specificbrain, prostate, muscles, lung…. Patient specific  Activity

  11. plasma muscle subcutan. t. patients healthy Tissue concentrations - patients • Imipenem 500mg • Microdialysis in muscle, subcutaneous tissue I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325

  12. Concentrations In The Lung – Cardiac Surgery Concentration in plasma Concentration in pulmonary interstitial fluid • PK/PD unbound AUCtissue/MIC ratio  30-40 • Levofloxacin 500 mg • Microdialysis in lung Lung:unbound AUCtissue/MIC ratio  1-4 for pseudomonas Hutschala D et al: AAC 2005, 49: 5107

  13. Time-kill curves for P. aeruginosa (MIC 0.12, 0.5, 2 mg/l) Interstitial fluid of subcutaneous adipose tissue (warmed + reference tissue) Concentration at site of infection  activity • Ciprofloxacin 200 mg • Increase of Microcirculatory Blood Flow Joukhadar C et al: AAC 2005, 49: 4149

  14. MIC 0,5 s 2 s 2 s s: NCCLS susceptible Placebo! Tissue concentration: middle ear • Haemophilus influenzae amox/clav cefaclor azithromycin R Dagan et al: AAC 2000, 44 (1)R Dagan et al: Pediatr Inf Dis J 2000, 19 (2)DM. Canafax et al: Pediatr Inf Dis J 1998, 17 (2)T Eden et al: Scand J Infect Dis 1983, Suppl, 39JO Klein, CID 1994,19 (5)

  15. non-specialized tissues specialized tissues serum interstitial fluid bound bound transport pump free drug free drug diffusional barriers equilibrium Protein binding • small reservoirs • large reservoirs

  16. Ertapenem Relationships between EC50 and % human serum for E. cloacae (•) and S. aureus () DE Nix et al. AAC 2004 (48) 3419 Protein binding • affects • Distribution • Tissue penetration • Clearance • Interactions • Activity

  17. Protein binding: Effect on Penetration of ß-Lactams into Rabbit Peripheral Lymph Correlation between protein binding and penetration 100 75 % Penetration of total drug (AUC lymph/AUC plasma 50 25 25 50 75 100 Plasma binding % G Woodnutt et al. AAC 1995, 39 (12)

  18. 35% 95% Protein Binding: Cefotaxime - Ceftriaxone g/ml h F Scaglione et al. JAC 1990, 26, Suppl A

  19. Protein binding • Telithromycin 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

  20. Protein binding >90% Oxacillin, ceftriaxone, ertapenem, teicoplanin, daptomycin, televancin, fusidic acid, rifapentine >70% Cefazolin, rifampicin, oritavancin >30% Penicillin G, cefixime, cefotaxime,erythromycin, clarithromycin, azithromycin, telithromycinvancomycin, linezolid >10% Amoxicillin, piperacillincefpodoxime, cefuroxime, ceftazidime, imipenemciprofloxacin, levofloxacin, gatifloxacin, metronidazole <10% Meropenem, doripenem, aminoglycosides, fosfomycin

  21. Summary: tissue concentration – protein binding • Tissue penetration: • Precondition for activity • Site of infection  location of antibiotic • Don`t mix separated pharmacokinetic compartments (homogenates!), results may be misleading! • Protein binding: • Free drug is active • Highly protein bound drugs have reduced antibacterial effect in vitro (with albumin) • Don’t correlate MIC (measured in protein-free media) with total concentrations • Protein binding influences tissue penetration • Drugs with high protein binding are not generally less clinically active

  22. Enjoy the meeting Whitehead`s rule:Seek simplicity, and distrust it. Take home message: • Consider free levels • Distrust tissue homogenates

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