Can pharmacokinetic–pharmacodynamic parameters provide dosing regimens that are less vulnerable to resistance?

ABSTRACTDissemination of antibiotic resistance in bacteria is associated with prescription of the corresponding drugs. Various pharmacokinetic–pharmacodynamic parameters have been developed with the intention of reducing the spread of resistance. In this review, it is considered whether dosing regimens based on these parameters can delay this spread. The evolution of bacterial resistance to antibiotics involves two successive but distinct and independent mechanisms. The first occurs by mutation in the genome, including the host chromosome and mobile accessory genetic elements such as plasmids or transposons, or, following acquisition of a resistance determinant from another bacterium, by horizontal gene transfer. These two genetic events happen by chance, which means that they do not rely on the presence of an antibiotic in the environment; that is, they are not induced, but simply revealed and propagated by the drugs. The second step is dissemination of resistance which can be due to the spread of bacteria (clonal epidemics), of replicons (plasmid epidemics) or of resistance determinants (gene epidemics). Resistance dissemination by each one of these three levels which superimpose in nature, is not only infectious but also exponential, since all three are associated with DNA replication (duplication) of the host chromosome, of a plasmid, or of a transposon. As opposed to emergence, dissemination is clearly associated with the selective pressure exerted by antibiotic prescription [1 and 2]. The consequence of this dual evolutionary pathway is that proper use of antibiotics will, at best, delay the spread of resistance. In this review, the pharmacokinetic–pharmacodynamic (PK–PD) parameters that are intended to lower resistance dissemination are considered exclusively.