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Therapeutisches Drug Monitoring und individualisierte Dosierung von Antibiotika bei der Sepsis

Modern oder nur „modisch“?

Therapeutic drug monitoring and individual dosing of antibiotics during sepsis

Modern or just “trendy”?

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Zusammenfassung

Schwere Sepsis und septischer Schock führen bei fast allen antiinfektiven Substanzen zu einer erheblichen Veränderung der substanzspezifischen Pharmakokinetik, die möglicherweise erheblich die Wirkortkonzentration und damit die Wirksamkeit der Antibiotika beeinflusst.

Um ein weites Spektrum möglicher Erreger beim kritisch Kranken sicher zu erfassen, werden Breitspektrumantibiotika in möglichst hohen Konzentrationen am Wirkort benötigt. Empfohlene Dosierungen und in Antibiogrammen ausgewiesene Sensibilitäten (sensibel, intermediär oder resistent getestet) beruhen auf der Annahme, dass die Pharmakokinetik des Arzneistoffs der eines „Normpatienten“ entspricht. Tatsächlich ist jedoch die Verteilung und Ausscheidungskapazität der Arzneistoffe beim kritisch Kranken sehr variabel und schwer vorhersehbar. Allein die Nierenfunktion von Patienten mit schweren Infektionen zeigt eine große inter- und intraindividuelle Variabilität, sodass die Arzneistoffclearance und damit die optimale Dosierung überwiegend renal ausgeschiedener Antiinfektiva um den Faktor 10 variieren kann. Vor dem Hintergrund der pathophysiologischen Veränderungen im Bereich der Pharmakokinetik (PK) bei schwerer Sepsis erscheinen individuelle Dosierungen und das Therapeutisches Drug-Monitoring (TDM) von β‑Lactam-Antibiotika wichtig, um eine zeitgerechte und adäquate antiinfektive Therapie sicherzustellen. Bei bekannter minimaler Hemmkonzentration (MHK) ist auf Basis gemessener Arzneistoff-Konzentrationen und der Zusammenhänge von PK und Pharmakodynamik (PD) (zeit-, konzentrationsabhängige Wirksamkeit) eine Einstellung auf optimale Serumspiegel möglich.

Die antiinfektive Therapie bei kritisch Kranken vor allem septischen Intensivpflegepatienten ist heute mehr als nur eine Frage der richtigen Substanz und einer zeitnahen Applikation. Individuelle Dosierung, prolongierte Applikation und therapeutisches TDM eröffnen möglicherweise neue, interessante Horizonte.

Abstract

Pharmacokinetic variability of anti-infective drugs due to pathophysiological changes by severe sepsis and septic shock is a well-known problem for critically ill patients resulting in suboptimal serum and most likely tissue concentrations of these agents.

To cover a wide range of potential pathogens, high concentrations of broad spectrum anti-infectives have to reach the site of infection. Microbiological susceptibility testing (susceptible, intermediate, resistant) don’t take the pharmacokinetic variability into account and are based on data generated by non-critically ill patients. But inter-patient variability in distribution and elimination of anti-infective drugs in ICU patients is extremely high and also highly unpredictable. Drug clearance of mainly renally eliminated drugs and thus the required dose can differ up to 10-fold due to the variability in renal function in patients with severe infections. To assure a timely and adequate anti-infective regime, individual dosing and therapeutic drug monitoring (TDM) seem to be appropriate tools in the setting of pathophysiological changes in pharmacokinetics (PK) and pharmakodynamics (PD) due to severe sepsis. In the case of known minimal inhibitory concentration, PK/PD indices (time or peak concentration dependent activity) and measured serum level can provide an optimal target concentration for the individual drug and patient.

Modern anti-infective management for ICU patients includes more than the choice of drug and prompt application. Individual dosing, optimized prolonged infusion time and TDM give way to new and promising opportunities in infection control.

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  1. Klinik für Anästhesie, operative Intensivmedizin und spezielle Schmerztherapie, Klinikum Heidenheim, Schlosshaustraße 100, 89522, Heidenheim, Deutschland

    A. Brinkmann MBA, A. Köberer & T. Fuchs

  2. Apotheke, Klinikum Heidenheim, Heidenheim, Deutschland

    A. C. Röhr, J. Preisenberger & O. R. Frey

  3. Klinik für Anästhesiologie und Operative Intensivmedizin, Klinikum Konstanz, Konstanz, Deutschland

    W. A. Krüger

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  1. A. Brinkmann MBA
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  2. A. C. Röhr
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  3. A. Köberer
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  4. T. Fuchs
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  5. J. Preisenberger
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  6. W. A. Krüger
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  7. O. R. Frey
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Correspondence to A. Brinkmann MBA.

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Interessenkonflikt

A. Brinkmann erhielt: Forschungsförderung von Fresenius Medical Care; Reisekostenunterstützung von Grünenthal, Pfizer, Niedersächsisches Landesgesundheitsamt, DAAF, PEG, BDA, DGAI, DIVI; Honorare für Vorträge von Grünenthal GmbH, Pfizer Pharma GmbH, Niedersächsisches Landesgesundheitsamt. J. Preisenberger gibt an, dass die Preisenberger UG für das CADDy-Projekt eine finanzielle Unterstützung von Fresenius Kabi Deutschland erhielt. A.C. Röhr, A. Köberer, T. Fuchs, W.A. Krüger und O.R. Frey geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Dieser Beitrag erschien in einer früheren Version in: J. Eckart, H. Forst, J. Briegel (Hrsg.) (2015) Intensivmedizin [11]. Der vorliegende Artikel wurde mit Genehmigung des ecomed-Verlages für die Publikation in dieser Zeitschrift aktualisiert und komplett überarbeitet.

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Brinkmann, A., Röhr, A.C., Köberer, A. et al. Therapeutisches Drug Monitoring und individualisierte Dosierung von Antibiotika bei der Sepsis. Med Klin Intensivmed Notfmed 113, 82–93 (2018). https://doi.org/10.1007/s00063-016-0213-5

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  • DOI: https://doi.org/10.1007/s00063-016-0213-5

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