Dosing

Emergence of resistance during therapy is a well known phenomenon that has been frequently described in ICU patients infected with P. aeruginosa. Until recently, it has not been common practice to consider the potential for selection of resistance when evaluating antibacterial drug exposure and the impact of antibiotic regimens or duration of therapy. Accumulating evidence confirms that dosage regimens focused only on reducing the susceptible bacterial population are clearly associated with a risk of selecting preexisting or newly formed mutants and allow complete replacement of the susceptible population with a resistant bacterial population. Emergence of resistance is also correlated to the duration of therapy. The longer the therapy continues, the more intense the drug exposure needs to be to maintain suppression of the less-susceptible subpopulation.

Several aspects determine the risk of emergence of resistance during therapy.
A few examples:

  • Drug exposure against less susceptible subpopulations
  • Dosing regimen that ensures active concentrations considering PK variability
  • Loading dose if steady state is not reached after the first dose (e.g. colistin)
  • Short duration of therapy (e.g. 5-7 days)
  • Inducible resistance (e.g. ampC especially in Enterobacter and cephalosporins)
  • Combinations if the therapeutic index is small and dosis cannot be increased

During antibiotic therapy, gradients of antibiotic concentrations are formed in the human body. These gradients will depend on the rates of drug diffusion into various tissues and the variation in the rate of elimination from different compartments. In the body, diverse environmental antibiotic selective pressures will, thus, be created, and the selection process can be expected to differ accordingly (SK Olofsson, O Cars, 2007).

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