[Pharmacokinetic and pharmacodynamic aspects in antibiotic treatment]

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.