Critically ill patients

Patients in the Intensive Care Unit are mostly critically ill and have a much higher level of sickness severity which is associated with profound pathophysiological changes and aggressive medical intervention. In particular, critically ill patients with sepsis, septic shock and/or acute kidney injury are considered to be significant challenge to medical professionals. Guidance for effective antibiotic dosing in critically ill patients is usually not included in treatment guidelines. Choosing antibiotic doses is usually based on dose-finding studies that are performed in healthy volunteers and non-critically ill patients. Severely altered pharmacokinetics in many critically ill patients causes an increased risk for inadequate drug exposure with reduced likelihood of positive clinical outcomes. Due to significant PK variability even optimised general dosing guidelines for ICU patients may not predict a therapeutic dose in an individual patient, potentially resulting in sub-optimal patient outcomes (R. Jason et al, submitted 2013).

Since the introduction of antibacterial drugs, dosing concepts have evolved considerably. Distinct refinements of dosing strategy have been incorporated into practice over time to deal more effectively with different patient groups and to retain the utility of particular drugs. These approaches include (in order of appearance):

  • Traditional: The empirical, one-dose-fits-all dose finding process was based on pharmacokinetic data from volunteers or non-critically ill patients. The licensed dose, usually the minimal dose that showed efficacy in Phase 3 clinical studies, is given to everyone according to some specified criteria (kidney function, age group, sometimes according to site of infection or severity of infection)
  • Optimized: Based on PK/PD principles the traditional licensed dosing recommendations were optimised, especially in specific patient groups, e.g. continuous infusion, increased dosages according to probability of target attainment
  • TDM: Dosing according to the above mentioned concepts but applying Therapeutic Drug Monitoring (TDM) at specific time points and adapting the dose according to individual information based on accepted criteria. TDM is usually restricted to vancomycin and aminoglycosides but could be extended to other antibacterial groups if the analytical capabilities and knowledge are available.
  • Individualized: More recently, individualized dosing from the first dose throughout the therapy is studied and applied in critical situations using decision tools based on Bayesian feedback approaches and TDM information. Such strategies beyond TDM based on individualizing dosing throughout the duration of therapy account for the large variability in PK but also allow for adapting to rapidly changing physiological conditions in such patients.

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