Impact of Severe Sepsis or Septic Shock on Drug Response

Several studies conducted in critically ill patients have demonstrated that inappropriate antibiotic treatment was associated with increased mortality (Niederman, 2006; Pea & Viale, 2009; Zilberberg et al., 2008). This fact was always related to the use of the wrong antimicrobial agent. However, the failure of a treatment might be due to inadequate doses that lead to sub-therapeutic concentrations at the infection site. This last issue is relevant in patients with severe sepsis or septic shock as many factors can influence pharmacokinetic variability and consequently human drug response. Among these factors we can mention the pathology itself. Only the knowledge of the pathogenesis of sepsis can enable us to understand the variability of drug concentrations with the aim of a successful therapeutic outcome avoiding therapeutic failure or toxicity. The sudden changes observed in severe sepsis or septic shock (increase in capillary permeability, edema formation, vasodilation and hypotension) and the therapeutic action taken to revert the situation (volume resuscitation, vasopressor agents) makes antibiotics or other drug concentrations difficult to interpret. Due to the lack of stable disease conditions, and consequently marked variations in pharmacokinetics parameters, dose dosage in these patients is a great challenge. The dynamic status of sepsis in critically ill patients results in alterations in pharmacokinetic parameters so it is of importance drug concentration assessment in this population, different from healthy volunteers or less severe ill patients. The use of nomograms to provide estimates for dosages is not advisable as they assume normal pharmacokinetic parameters and due to instability of the system, pharmacokinetic parameters are subject to rapid changes. As the measurement of total drug concentration (free drug plus protein-bound drug) is much easier and cheaper than free drug determination, therapeutic drug monitoring is usually based on total plasma concentrations. However, only the free drug is capable of diffusing into the biophase, only the free drug is responsible for the therapeutic effect. This fact has to be taken into account to see if the changes provoked by sepsis itself impact on both total drug and free drug in the same way. If this is not the case, defining dose regimens only by plasma total drug concentrations could be erroneous.