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T issue concentrations Protein binding

1 2 th ISAP Educational Workshop, Copenhagen 2005. T issue concentrations Protein binding. Ursula Theuretzbacher Center for Anti-Infective Agents, Vienna. Tissue penetration - protein binding. High tissue concentrations!??. Int J Clin Pharmacol Ther. 2003 Jun;41(6):267-74.

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T issue concentrations Protein binding

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  1. 12th ISAP Educational Workshop, Copenhagen 2005 Tissue concentrationsProtein binding Ursula TheuretzbacherCenter for Anti-Infective Agents, Vienna

  2. Tissue penetration - protein binding High tissue concentrations!?? 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. Where is the antibiotic ? Where is the pathogen ? Active concentration(protein binding!) Tissue penetration - protein binding

  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 Where is the pathogen?

  5. blood capillary homogenates,biopsies cells 70-80% • intravascular • extra-, intracellular • Bound + free fraction 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.“ Where is the antibiotic? 20-30%

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

  7. Imipenem Compartment specific plasma microdialysis muscle subcutan. t. extracellularintracellular healthy patients intracellular compartments I. Tegeder et al. Clin Pharmacol Ther. 2002 71(5):325 Tissue concentrations • Tissue specificbrain, prostate, muscles, lung…. Patient specific  Activity

  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. Clarithromycin: 2x 500mg, 4 days Azithromycin: 1x 500mg /1x 250mg, 4 days Tissue concentration: pulmonary g/ml h 4 8 12 24 K Rodvold et al. AAC, 1997, 41 (6)

  10. 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)

  11. 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)

  12. 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

  13. activity! S Tawara et al. AAC 1992, 36 (1) Protein binding • affects • distribution • tissue penetration • clearance • interactions

  14. 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)

  15. 35% 95% Protein Binding: Cefotaxime - Ceftriaxone g/ml h F Scaglione et al. JAC 1990, 26, Suppl A

  16. Protein binding • Telithromycin • Ertapenem Mean time-versus-concentration profiles of total and free telithromycin in plasma, muscle, and subcutis (800 mg p.o.) Relationships between EC50 and % human serum for E. cloacae (•) and S. aureus () R. Gattringer et al. AAC 2004 (48) 4650 DE Nix et al. AAC 2004 (48) 3419

  17. Protein binding • Azoles D. Andes: Infect Dis Clin N Am 2003 (17) 635

  18. 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

  19. 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

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

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