Zusammenfassung
Die schwere Sepsis und der septische Schock haben eine hohe Mortalität und erfordern daher eine rasch wirksame verträgliche antibiotische Therapie. Aufgrund pathophysiologischer Vorgänge im Rahmen einer Sepsis kann sich die Pharmakokinetik verändern. Vor allem wasserlösliche Substanzen haben am Beginn einer schweren Sepsis ein erhöhtes Verteilungsvolumen, weshalb eine hohe Anfangsdosis erforderlich ist. Auch die renale Ausscheidung kann zunächst erhöht sein. Im weiteren Krankheitsverlauf kommt es häufig zu Organschäden mit verminderter Elimination, was eine neuerliche Dosisanpassung erfordert. Die Antibiotikaklassen unterscheiden sich in ihren relevanten pharmakokinetisch-pharmakodynamischen Zielparametern. Spitzenkonzentration, Expositionszeit oder Gesamtexposition, ausgedrückt durch die Fläche unter der Konzentrations-Zeit-Kurve, können für ihre Wirksamkeit ausschlaggebend sein. Bei der Behandlung mit zeitabhängigen Antibiotika (z. B. mit β-Lactamen) sollte der Wirkspiegel möglichst konstant über der minimalen Hemmkonzentration (MHK) gehalten werden, was eine häufigere, eventuell auch eine kontinuierliche Verabreichung nahelegt. Bei konzentrationsabhängigen Substanzen (z. B. bei Aminoglykosiden) ist die Höhe der Einzeldosis maßgeblich, während das Dosisintervall angepasst werden kann. Wechselwirkungen mit Antibiotika werden v. a. durch Hemmung des Abbaus, insbesondere von Cytochrom-P-450-Isoenzymen sowie durch Summation toxischer Effekte hervorgerufen. Sie können zu schweren Komplikationen, wie Nierenversagen oder ventrikulären Rhythmusstörungen, führen. Eine Enzyminduktion kann subtherapeutische Spiegel bewirken. Ist eine kontinuierliche Ersatztherapie notwendig, sind die Antibiotikadosierungen entsprechend den Ergebnissen einschlägiger Studien anzupassen.
Abstract
Severe sepsis and septic shock have a high mortality and, therefore require fast and effective antibiotic treatment with low toxicity. Because of sepsis-induced pathophysiological changes, pharmacokinetics of antimicrobial agents can be altered. Particularly water-soluble drugs display an enhanced volume of distribution during early sepsis. Therefore high loading doses are necessary. Renal clearance can also be increased at this time. Later on, organ damage frequently occurs resulting in delayed drug elimination which requires further dose adjustment. The different classes of antibiotics differ in their relevant pharmacokinetic–pharmacodynamic target parameters. Thus, the efficacy of an antimicrobial agent can depend on its concentration, on the exposure time, and on the total exposure as expressed by the area under the time–concentration curve. During treatment with time-dependent antibiotics (e.g. β-lactams), their concentration should be maintained above the minimal inhibitory concentration (MIC) warranting more frequent administration or continuous infusion. For concentration dependent agents (e.g. aminoglycosides), the single dose is pivotal, whereas the dosage interval can be extended. Drug–drug interactions involving antibiotics are mainly caused by inhibition of their metabolism, particularly of cytochrome P 450 iso-enzymes, or by additive toxic effects. They can result in severe complications such as renal failure or ventricular arrhythmias. Conversely, enzyme induction may lead to subtherapeutic drug levels. When continuous renal replacement therapy is required, the dosage of antibiotics has to be adapted according to the results of respective pharmacokinetic studies.
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Interessenkonflikt. R. Bellmann gibt an, Forschungsunterstützungen und Vortragshonorare von den Firmen Chiesi Pharmaceuticals, Pfizer, und Merck, Sharp und Dohme erhalten zu haben.
Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.
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Bellmann, R. Pharmakokinetische und pharmakodynamische Aspekte bei der Antibiotikatherapie. Med Klin Intensivmed Notfmed 109, 162–166 (2014). https://doi.org/10.1007/s00063-013-0308-1
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DOI: https://doi.org/10.1007/s00063-013-0308-1