Skip to main content
SpringerLink
Log in

Gewebepenetration von Antibiotika

Erreicht die Behandlung den Zielort?

Tissue penetration of antibiotics

Does the treatment reach the target site?

  • Leitthema
  • Published:
Medizinische Klinik - Intensivmedizin und Notfallmedizin Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

Infektionen stellen bei kritisch kranken Patienten nach wie vor eine besondere Herausforderung für den behandelnden Arzt dar. Einer der Schlüsselfaktoren für therapeutischen Erfolg sind suffiziente Konzentrationen des eingesetzten Antibiotikums am Ort der Infektion. Zumeist ist dies der interstitielle Raum des betroffenen Organs oder ein Körperhohlraum, wesentlich seltener sind vitale Bakterien innerhalb von Körperzellen lokalisiert.

Material und Methoden

Verschiedene Methoden zur Bestimmung von Gewebekonzentrationen antimikrobieller Substanzen, darunter die Gewebebiopsie, die bronchoalveoläre Lavage und die Mikrodialyse, werden vorgestellt und die Implikationen für die Interpretation der gewonnen Daten besprochen. Exemplarisch werden Gewebekonzentrationen des hydrophilen β-Lactams Meropenem und des lipophilen Chinolons Levofloxacin gegenübergestellt und diskutiert.

Ergebnisse

Es zeigt sich, dass sowohl zwischen Plasma und Gewebe, gesunden Probanden und schwerkranken Patienten als auch zwischen den durch verschiedene Methoden im gleichen Organ erhobenen pharmakokinetischen Daten relevante Unterschiede bestehen.

Schlussfolgerungen

Eine kritische Interpretation der Daten, die von der Art des Erregers, der Lokalisation der Infektion sowie der zur Bestimmung der Gewebekonzentration eingesetzten Methodik abhängen muss, wird angeregt, um Wissen über die Pharmakokinetik einer Substanz im Gewebe optimal in der Behandlung schwerkranker Patienten einsetzen zu können.

Abstract

Background

For critically ill patients, infections still imply a major challenge for the treating physician. One key factor of successful treatment is sufficient exposure of the employed antimicrobial agent at the site of infection. In most cases, this is the interstitial space of the infected organ or a body cavity; much rarer vital bacteria are located within body cells.

Methods

Different methods for assessment of tissue pharmacokinetics of antimicrobial agents in the human body are described, including tissue biopsy, bronchoalveolar lavage and microdialysis, and their implication on interpretation of obtained data are discussed. Tissue pharmacokinetics of the hydrophilic beta-lactam meropenem and the lipophilic fluoroquinolone levofloxacin are compared.

Results

Differences in pharmacokinetics between plasma and tissue, healthy volunteers and critically ill patients but also between data obtained in the same organ by different methods are discussed.

Conclusion

In order to use pharmacokinetic data to optimize the treatment of critically ill patients, critical appraisal of the causative pathogen, the location of the infection, and the source of the used pharmacokinetic data is necessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Literatur

  1. Andrews JM, Honeybourne D, Jevons G et al (1997) Concentrations of levofloxacin (HR 355) in the respiratory tract following a single oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 40:573–577

    Article  CAS  PubMed  Google Scholar 

  2. Bergogne-Berezin E, Muller-Serieys C, Aubier M et al (1994) Concentration of meropenem in serum and in bronchial secretions in patients undergoing fibreoptic bronchoscopy. Eur J Clin Pharmacol 46:87–88

    Article  CAS  PubMed  Google Scholar 

  3. Brun-Buisson C, Meshaka P, Pinton P et al (2004) EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 30:580–588

    Article  CAS  PubMed  Google Scholar 

  4. Brunner M, Langer O (2006) Microdialysis versus other techniques for the clinical assessment of in vivo tissue drug distribution. AAPS J 8:E263–E271

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Brunner M, Pernerstorfer T, Mayer BX et al (2000) Surgery and intensive care procedures affect the target site distribution of piperacillin. Crit Care Med 28:1754–1759

    Article  CAS  PubMed  Google Scholar 

  6. Byl B, Jacobs F, Roucloux I et al (1999) Penetration of meropenem in lung, bronchial mucosa, and pleural tissues. Antimicrob Agents Chemother 43:681–682

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Capitano B, Mattoes HM, Shore E et al (2004) Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults. Chest 125:965–973

    Article  CAS  PubMed  Google Scholar 

  8. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10 (quiz 11–12)

    Article  CAS  PubMed  Google Scholar 

  9. Dagan R, Velghe L, Rodda JL et al (1994) Penetration of meropenem into the cerebrospinal fluid of patients with inflamed meninges. J Antimicrob Chemother 34:175–179

    Article  CAS  PubMed  Google Scholar 

  10. Davis R, Bryson HM (1994) Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 47:677–700

    Article  CAS  PubMed  Google Scholar 

  11. Elmquist WF, Sawchuk RJ (1997) Application of microdialysis in pharmacokinetic studies. Pharm Res 14:267–288

    Article  CAS  PubMed  Google Scholar 

  12. EMEA (2000) Points to consider on pharmacokinetics and pharmacodynamics in the development of antibacterial medicinal products. http://www.tga.gov.au/pdf/euguide/ewp265599en.pdf. Zugegriffen: 17. März 2014

  13. FDA (1998) Guidance for Industry. Developing antimicrobial drugs – general considerations for clinical trials. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070983.pdf. Zugegriffen: 17. März 2014.

  14. Fish DN, Chow AT (1997) The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet 32:101–119

    Article  CAS  PubMed  Google Scholar 

  15. Frimodt-Moller N (2002) How predictive is PK/PD for antibacterial agents? Int J Antimicrob Agents 19:333–339

    Article  CAS  PubMed  Google Scholar 

  16. Fujita A, Miya T, Tanaka R et al (1999) Levofloxacin concentrations in serum, sputum and lung tissue: evaluation of its efficacy according to breakpoint. Jpn J Antibiot 52:661–666

    Article  CAS  PubMed  Google Scholar 

  17. Goncalves-Pereira J, Povoa P (2011) Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of beta-lactams. Crit Care 15:R206

    Article  PubMed Central  PubMed  Google Scholar 

  18. Gotfried MH, Danziger LH, Rodvold KA (2001) Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Chest 119:1114–1122

    Article  CAS  PubMed  Google Scholar 

  19. Hukagawa H, Noga K (1992) A study on the concentrations of levofloxacin in the gallbladder tissue and bile of patients. Jpn J Antibiot 45:253–257

    CAS  PubMed  Google Scholar 

  20. Joukhadar C, Frossard M, Mayer BX et al (2001) Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 29:385–391

    Article  CAS  PubMed  Google Scholar 

  21. Joukhadar C, Klein N, Mayer BX et al (2002) Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis. Crit Care Med 30:1478–1482

    Article  CAS  PubMed  Google Scholar 

  22. Karjagin J, Lefeuvre S, Oselin K et al (2008) Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock. Clin Pharmacol Ther 83:452–459

    Article  CAS  PubMed  Google Scholar 

  23. Kearney BP, Aweeka FT (1999) The penetration of anti-infectives into the central nervous system. Neurol Clin 17:883–900

    Article  CAS  PubMed  Google Scholar 

  24. Kitzes-Cohen R, Farin D, Piva G et al (2002) Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Int J Antimicrob Agents 19:105–110

    Article  CAS  PubMed  Google Scholar 

  25. Marcy TW, Merrill WW, Rankin JA et al (1987) Limitations of using urea to quantify epithelial lining fluid recovered by bronchoalveolar lavage. Am Rev Respir Dis135:1276–1280

    Google Scholar 

  26. Nishikawa G, Ikawa K, Nakamura K et al (2013) Prostatic penetration of meropenem in humans, and dosage considerations for prostatitis based on a site-specific pharmacokinetic/pharmacodynamic evaluation. Int J Antimicrob Agents 41:267–271

    Article  CAS  PubMed  Google Scholar 

  27. Pea F, Pavan F, Nascimben E et al (2003) Levofloxacin disposition in cerebrospinal fluid in patients with external ventriculostomy. Antimicrob Agents Chemother 47:3104–3108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Rennard SI, Basset G, Lecossier D et al (1986) Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol 60:532–538

    CAS  PubMed  Google Scholar 

  29. Robatel C, Decosterd LA, Biollaz J et al (2003) Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. J Clin Pharmacol 43:1329–1340

    Article  CAS  PubMed  Google Scholar 

  30. Roberts JA, Kirkpatrick CM, Roberts MS et al (2009) Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 64:142–150

    Article  CAS  PubMed  Google Scholar 

  31. Ryan DM (1993) Pharmacokinetics of antibiotics in natural and experimental superficial compartments in animals and humans. J Antimicrob Chemother 31(Suppl D):1–16

    Article  CAS  PubMed  Google Scholar 

  32. Sauermann R, Delle-Karth G, Marsik C et al (2005) Pharmacokinetics and pharmacodynamics of cefpirome in subcutaneous adipose tissue of septic patients. Antimicrob Agents Chemother 49:650–655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Tomaselli F, Maier A, Matzi V et al (2004) Penetration of meropenem into pneumonic human lung tissue as measured by in vivo microdialysis. Antimicrob Agents Chemother 48:2228–2232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Vogelman B, Gudmundsson S, Leggett J et al (1988) Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 158:831–847

    Article  CAS  PubMed  Google Scholar 

  35. Zeitlinger BS, Zeitlinger M, Leitner I et al (2007) Clinical scoring system for the prediction of target site penetration of antimicrobials in patients with sepsis. Clin Pharmacokinet 46:75–83

    Article  CAS  PubMed  Google Scholar 

  36. Zeitlinger M, Muller M, Joukhadar C (2005) Lung microdialysis – a powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review). Aaps J 7:E600–E608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Zeitlinger MA, Dehghanyar P, Mayer BX et al (2003) Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis. Antimicrob Agents Chemother 47:3548–3553

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Zeitlinger MA, Erovic BM, Sauermann R et al (2005) Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis. J Antimicrob Chemother 56:703–708

    Article  CAS  PubMed  Google Scholar 

  39. Zeitlinger MA, Traunmuller F, Abrahim A et al (2007) A pilot study testing whether concentrations of levofloxacin in interstitial space fluid of soft tissues may serve as a surrogate for predicting its pharmacokinetics in lung. Int J Antimicrob Agents 29:44–50

    Article  CAS  PubMed  Google Scholar 

  40. Zhanel GG, Dueck M, Hoban DJ et al (2001) Review of macrolides and ketolides: focus on respiratory tract infections. Drugs 61:443–498

    Article  CAS  PubMed  Google Scholar 

  41. http://en.wikipedia.org/wiki/File:Schematic_illustration_of_a_microdialysis_probe.png#metadata. Zugegriffen: 17. März 2014

Download references

Einhaltung ethischer Richtlinien

Interessenkonflikt. H. Lagler und M. Zeitlinger geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Author information

Authors and Affiliations

  1. Klinische Abteilung für Infektionen & Tropenmedizin, Universitätsklinik für Innere Medizin I, Allgemeines Krankenhaus (AKH), Medizinische Universität Wien, Wien, Österreich

    H. Lagler

  2. Universitätsklinik für Klinische Pharmakologie, Allgemeines Krankenhaus (AKH), Medizinische Universität Wien, Währinger Gürtel 18–20, 1090, Wien, Österreich

    M. Zeitlinger

Authors
  1. H. Lagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Zeitlinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Zeitlinger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lagler, H., Zeitlinger, M. Gewebepenetration von Antibiotika. Med Klin Intensivmed Notfmed 109, 175–181 (2014). https://doi.org/10.1007/s00063-013-0309-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00063-013-0309-0

Schlüsselwörter

Keywords

Search

Navigation